Tricyclic compound and use thereof

ABSTRACT

The present invention relates to the compound represented by formula (I): 
                         
(wherein, all the symbols have the same meaning as that of the specification), a salt thereof, a solvate thereof or a prodrug thereof. Since the compound of the present invention has an anti stress action, it is useful for preventive and/or therapeutic agent for a disease caused by stress, especially a digestive system disease caused by stress and is superior to oral absorption.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation application of U.S. application Ser. No.13/097,741 filed Apr. 29, 2011 (allowed), which is a divisionalapplication of U.S. application Ser. No. 11/722,623 filed Jun. 22, 2007(U.S. Pat. No. 7,964,726), which is a 371 National Stage entry ofPCT/JP2005/023450 filed Dec. 21, 2005, which claims priority of JapaneseApplication Nos. 2004-371033 filed Dec. 22, 2004 and 2005-261914 filedSep. 9, 2005. The above-noted applications are incorporated herein byreference in their entirety.

TECHNICAL FIELD

The present invention relates to a tricyclic heterocyclic ring compounduseful for preventing and/or treating for a disease caused by stress,process for preparation thereof and use thereof.

BACKGROUND ART

A disease caused by stress means that by psychosocial or physical stressstimulation (stressor), the distortion (response to stress) in the bodysubjected to these stimulations occurs and any disorders in systemicvarious areas develop. Concretely, since stressor influences (responseto stress) on the activities of nervous system, endocrine system andimmune system to void these functions, these influences lead to organiclesions in brain itself or peripheral organs. In case of being subjectedto excess stress, it causes diseases leading to marked reduce of qualityof life (so-called, QOL).

Diseases caused by stress include, for example, central nervous systemdiseases (e.g. depression etc.), digestive system diseases (e.g.irritable bowel syndrome, gastric ulcer etc.), cardiovascular systemdiseases (e.g. essential hypertension etc.) and the like. As medicinaldrugs for remedy for diseases caused by these stresses, anti depressantdrug, anti anxiety drug and drug for symptomatic treatment againstorganic lesions of peripheral organs (e.g. antacids, gastricmucoprotective drugs etc.) have been developed for the purpose ofalleviating psychological stressor. However, these drugs becomeeffective to some extent, but these addictions, side effects or the likefrequently develop. At present, the therapy for these diseases comes todefinitive therapy. Therefore, the development of the preventing and/ortherapeutic drug for diseases caused by stress having highly safety andcoming to possible definitive therapeutic drug has been longed for.

Meanwhile, there are mitochondrial benzodiazepine receptor (hereinafter,it is abbreviated as MBR.) (“Science 198, 849-851, 1977”, “Proc. Natl.Acad. Sci., 89, 3805-3809, 1977”) in mitochondrial outer membrane, whichtransport cholesterol from intracellular to the internal membrane ofmitochondria that is the active site of P-450 sec. Steroid synthesizedin the brain is called as neurosteroid. Cholesterol, which is thesteroid precursor, is converted into pregnenolone metabolized withside-chain cleavage enzyme P-450 scc. This process is the first processof steroid production system. However, it has been indicated that thistransport process was the rate determining process in steroid productionsystem rather than metabolism with P-450 scc. It has been thought thatthe neurosteroid content in the brain could be adjusted if the functionof MBRs could be regulated. It has been thought that as a result ofbalance between an excitatory signaling system and an inhibitorysignaling system was collapsed by neurosteroid content in the brainvarying under stress condition, the various stress-related diseasescould be caused by changes of activities in nerve system, immune systemand endocrine system which were regulated by these nerve systems.

As mentioned above, the disrupted balance between an excitatorysignaling system and an inhibitory signaling system caused by stress orload can be improved to the desirable balanced condition by the increaseor the inhibition of neurosteroid production, which is useful forprevention or treatment for stress-related diseases. Therefore, it isexpected that the compounds having affinity for MBRs are extremelyuseful for prevetion and/or treatment for these diseases, if they aresupplied

As the preventive and/or therapeutic agent for a disease caused bystress, the compound represented by formula (Y):A^(Y)-X^(Y)—Y^(Y)—Z^(Y)—B^(Y)  (Y)(wherein, A^(Y) is cyclic group which may have a substituent(s), X^(Y),Y^(Y) and Z^(Y) are each independently single bond or a spacer of whichmain chain has an atom number of 1-3, B^(Y) is hydrocarbon which mayhave a substituent(s) or cyclic group which may have a substituent(s)),a salt thereof, a N-oxide thereof, a solvate thereof or a prodrugthereof is known to have the affinity to MBRs (see, WO04/113300).

In addition, as tri-cyclic compound (β-carboline derivative), thecompounds represented by formula (Z):

(wherein, R^(0Z) is halogen atom, C1-6 alkyl etc.; R^(1Z) is aryl whichmay be substituted etc.; R^(2Z) is hydrogen atom, C1-6 alkyl etc.;R^(3Z) is hydrogen atom, C1-6 alkyl, aryl etc.; X^(Z) is C(═O), SO₂,C(═O)NR^(aZ) etc.; Y is (CH₂)_(nZ) aryl etc.; nZ is 0-4), apharmaceutically acceptable salt thereof or a solvate thereof has beenknown as phosphodiesterase inhibitor (see, WO02/064591).

DISCLOSURE OF THE INVENTION The Problems to be Solved by the Invention

As the preventive and/or therapeutic agent for a disease caused bystress, the development of the compound having anti stress effect andsuperior oral absorption has been longed for.

Means to Solve the Problem

As a result of the present inventors made further investigation to findout the compound having the affinity for MBRs as the preventive and/ortherapeutic agent for a disease caused by stress, they found out thatthe compounds of the present invention represented by formula (I) hadthe affinity to MBRs and anti stress effect. Furthermore, they found outespecially the compound of the present invention represented by formula(I-B-1-1) among the compound of the present invention represented byformula (I) shown strong anti stress effect in in vivo model and hadsuperior oral absorption, and completed the present invention.

That is, the present invention relates to

[1] A compound represented by formula (I):

wherein R¹ is a hydrogen atom(s) or a substituent(s),

t is 0 or an integer of 1 to 8, when t is 2 or more, R¹s are same ordifferent, two R¹s may together form a cyclic group which may have asubstituent(s);

R², R³, R⁴, R⁵, R⁶ and R⁷ are each independently a hydrogen atom(s) or asubstituent(s), R⁴ and R⁵ and/or R⁶ and R⁷ may form a cyclic group whichmay have a substituent(s) together with their binding carbon atom;

ring A¹ is a monocyclic carbocyclic ring or a monocyclic heterocyclicring;

ring A² is a cyclic group which may have a substituent(s);

B is a hydrogen atom, a hydrocarbon group which may have asubstituent(s) or a cyclic group which may have a substituent(s);

X and Z are each independently a bond, C1-3 alkylene which may have asubstituent(s), C2-3 alkenylene which may have a substituent(s) or C2-3alkynylene which may have a substituent(s);

Y is a bond, —C(═O)—, —C(═S)—, —C(═O)NR⁸—, —C(═S)NR⁸—, —SO₂—, —C(═O)O—or —SO₂NR⁸— group wherein X binds to a left side of each group,

R⁸ is a hydrogen atom or a substituent;

m is 0 or 1;

is a single bond or a double bond wherein 1) a and b are not a doublebond at the same time, 2) when m is 0, b is a double bond, 3) when m is1, b is a single bond, a salt thereof, an N-oxide thereof, a solvatethereof, or a prodrug thereof,

[2] The compound according to above [1], wherein R⁴ and R⁵ form a cyclicgroup which may have a substituent(s) together with their binding carbonatom, a salt thereof, an N-oxide thereof, a solvate thereof, or aprodrug thereof,

[3] The compound according to above [1], wherein ring A¹ is a monocyclicheterocyclic ring, a salt thereof, an N-oxide thereof, a solvatethereof, or a prodrug thereof;

[4] The compound according to above [1], wherein ring A¹ is a monocycliccarbocyclic ring, a salt thereof, an N-oxide thereof, a solvate thereof,or a prodrug thereof,

[5] The compound according to above [1], wherein X is a bond, a saltthereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof,

[6] The compound according to above [1], wherein Y is —C(═O)— or—C(═O)NR⁸— wherein X binds to a left side of each group, a salt thereof,an N-oxide thereof, a solvate thereof, or a prodrug thereof,

[7] The compound according to above [1], wherein Z is a bond or C1-3alkylene which may have a substituent(s), a salt thereof, an N-oxidethereof, a solvate thereof, or a prodrug thereof,

[8] The compound according to above [1], wherein B is C1-8 alkyl whichmay have a substituent(s), C3-10 monocyclic or bicyclic aromaticcarbocyclic which may have a substituent(s), a carbocyclic ring which ispartially or fully saturated, or 3-10 membered monocyclic or bicyclicaromatic heterocyclic ring which may be partially or fully saturated,and which contains 1 to 4 hetero atom(s) selected from an oxygen atom, anitrogen atom and/or a sulfur atom, a salt thereof, an N-oxide thereof,a solvate thereof, or a prodrug thereof,

[9] The compound according to above [1], which is a compound representedby formula (I-A):

wherein all the symbols have the same meanings as described in [1], asalt thereof, an N-oxide thereof, a solvate thereof, or a prodrugthereof,

[10] The compound according to above [9], which is a compoundrepresented by formula (I-A-1):

wherein R^(1A) has the same meaning as R¹;

tB is 0 or an integer of 1 to 3, when tB is 2 or more, R¹s are same ordifferent;

other symbols have the same meanings as described in above [1],

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrugthereof,

[11] The compound according to above [1], which is a compoundrepresented by formula (I-B-1):

wherein tA is 0 or an integer of 1 to 4, when tA is 2 or more, R¹s aresame or different;

R⁴ and R⁵ form cyclic group which may have a substituent(s) togetherwith their binding carbon atom;

other symbols have the same meanings as described in above [1],

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrugthereof,

[12] The compound according to above [1], which is a compoundrepresented by formula (I-B-2):

wherein all symbols have the same meaning as described in above [1] or[10],

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrugthereof,

[13] The compound according to above [11], which is a compoundrepresented by formula (I-B-1-1):

wherein B² is C1-8 alkyl which may have a substituent(s);

D is an atom which constitutes ring A² and is a carbon atom or anitrogen atom,

is a cyclic group which has at least two same or different substituents;

other symbols have the same meanings as described in above [1] or [11],a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrugthereof,

[14] The compound according to above [13], wherein

is a cyclic group which has two same or different substituents, a saltthereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof,

[15] The compound according to above [14],

wherein one substituent on ring A² is (1) C1-8 alkoxy which may have asubstituent(s), or (2) C3-7 cycloalkyloxy which may have asubstituent(s);

the other substituent is selected from (1) a halogen atom, (2) cyano,(3) C1-8 allyl which may have a substituent(s) and (4) C1-8 alkoxy whichmay have a substituent(s),

a salt thereof; an N-oxide thereof, a solvate thereof, or a prodrugthereof;

[16] The compound according to above [15],

wherein one substituent on ring A² is selected from (1) methoxy whichmay have a fluorine atom(s), (2) isopropoxy which may have a fluorineatom(s), (3) cyclopentyloxy which may have a fluorine atom(s);

the other substituent is selected from (1) a fluorine atom, (2) achlorine atom, (3) cyano, (4) methyl, and (5) methoxy which may have afluorine atom(s),

a salt thereof; an N-oxide thereof; a solvate thereof, or a prodrugthereof;

[17] The compound according to above [14], wherein the cyclic grouprepresented by

is a benzene ring, a salt thereof, an N-oxide thereof, a solvatethereof, or a prodrug thereof,

[18] The compound according to above [13], wherein one substituent issubstituted to an atom neighboring D, a salt thereof, an N-oxidethereof, a solvate thereof, or a prodrug thereof,

[19] The compound according to above [13], which is a compoundrepresented by formula (I-B-1-1-a):

wherein

is β-configuration and other symbols have the same meanings as describedin above [13],

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrugthereof,

[20] The compound according to above [14], which is a compoundrepresented by formula (I-B-1-2):

wherein R²⁰¹ is C1-8 alkoxy which may have a substituent(s) or C3-7cycloalkyl which may have a substituent(s);

R²⁰² is a halogen atom, cyano, C1-8 alkyl which may have asubstituent(s) or C1-8 alkoxy which may have a substituent(s);

other symbols have the same meanings as described in above [11],

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrugthereof,

[21] The compound according to above [20], which is a compoundrepresented by formula (I-B-1-2-a):

wherein all symbols have the same meanings as described in above [11],[19] or [20],

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrugthereof,

[22] The compound according to above [20] or [21],

wherein R²⁰¹ is selected from (1) methoxy which may have a fluorineatom(s), (2) isopropoxy which may have a fluorine atom(s), and (3)cyclopentyloxy which may have a fluorine atom(s);

R²⁰² is selected from (1) a fluorine atom, (2) a chlorine atom, (3)cyano, (4) methyl, and (5) methoxy which may have a fluorine atom(s),

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrugthereof.

[23] The compound according to above [1], which is

-   (1)    1-(1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide,-   (2)    2-acetyl-1-(2,4-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (3)    2-acetyl-1-(3,4-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (4)    2-acetyl-1-(3-fluorophenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (5)    2-acetyl-6-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (6)    2-acetyl-1-(2,4-difluorophenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (7)    2-acetyl-1-(3,4-difluorophenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (8)    2-acetyl-1-(3-fluorophenyl)-7-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (9)    2-acetyl-7-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (10)    2-acetyl-1-(3-fluorophenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (11)    1-(2,6-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2    (3H)-carboxamide,-   (12)    1-(3,5-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2    (3H)-carboxamide,-   (13)    1-(2,4-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide,-   (14) 1-(2,3-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydro spire    [β-carboline-4,1′-cyclopropane]-2 (3H)-carboxamide,-   (15)    1-(2,5-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide,-   (16)    1-(3,4-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide,-   (17)    6-chloro-N-(3,5-dimethylphenyl)-1-(3-fluorophenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide,-   (18)    N-(3,5-dimethylphenyl)-1-(3-fluorophenyl)-6-methoxy-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide,-   (19)    2-acetyl-1-(3-fluorophenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (20) 2-acetyl-1-(2,4-di    fluorophenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (21)    2-acetyl-1-(2,4-difluorophenyl)-7-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (22)    2-acetyl-1-(3,4-difluorophenyl)-7-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (23)    2-acetyl-5-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (24)    2-acetyl-1-(2,4-difluorophenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (25)    2-acetyl-1-(3,4-difluorophenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (26)    2-acetyl-1-(3-fluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (27)    2-acetyl-1-(2,4-difluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (28)    2-acetyl-1-(3,4-difluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (29)    2-acetyl-1-(3-fluorophenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (30)    2-acetyl-1-(3,4-difluorophenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (31)    8-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide,-   (32)    N-(3,5-dimethylphenyl)-8′-(3-fluorophenyl)-1′,8′-dihydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]-7′(6′H)-carboxamide,-   (33)    N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-9-methyl-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide,-   (34)    N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide,-   (35)    N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridine-7-carboxamide,-   (36)    7-acetyl-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridine,-   (37)    N-(3,5-dimethylphenyl)-8′-(3-fluorophenyl)-1′-methyl-1′,8′-dihydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]-7′(6′H)-carboxamide,-   (38)    7′-acetyl-8′-(3-fluorophenyl)-1′-methyl-1′,6′,7′,8′-tetrahydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine,-   (39)    N-(3,5-dimethylphenyl)-8-(3-methoxyphenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide,-   (40)    8-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide,-   (41)    N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxamide,-   (42)    2-chloro-N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxamide,-   (43)    N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxamide,-   (44)    7-acetyl-2-chloro-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine,-   (45)    7-acetyl-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine,-   (46)    2-ethyl-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (48)    2-acetyl-5-methoxy-1-(2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],    or-   (49)    4-(2-acetyl-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)benzonitrile,-   a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug    thereof,

[24] The compound as according to above [13], which is

-   (1)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (2)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (3)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (4)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (5)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (6)    2-acetyl-5-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (7)    2-acetyl-5-chloro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (8)    2-acetyl-5-fluoro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (9)    2-acetyl-6-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (10)    2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (11)    2-acetyl-1-(5-fluoro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (12)    2-acetyl-1-(4-fluoro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (13)    2-acetyl-1-(2,4-dimethoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-   (14)    2-acetyl-1-(2-fluoro-6-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (15)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (16)    2-acetyl-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (17)    2-acetyl-5-fluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (18)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (19)    2-acetyl-1-(4-fluoro-2-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (20)    2-acetyl-6-methoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (21)    2-acetyl-1-(2-fluoro-6-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (22)    2-acetyl-6,7-dimethoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (23)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (24)    2-acetyl-1-(2-methoxy-4-methylphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (25)    2-acetyl-1-(2,3-dihydro-1-benzofuran-7-yl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (26)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (27)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-   (28)    (18)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[carboline-4,1′-cyclopropane],-   (29)    (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (30)    (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (31)    (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (32)    (+)-2-acetyl-1-(2-fluoro-6-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (33)    (+)-2-acetyl-5-fluoro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (34)    (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (35)    2-acetyl-5-chloro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (36)    2-acetyl-5,6-difluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (37)    2-acetyl-5,6-difluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (38)    2-acetyl-5-chloro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (39)    2-acetyl-1-(4-chloro-2-isopropoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (40)    2-acetyl-1-[4-chloro-2-(cyclopentyloxy)phenyl]-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (41)    4-(2-acetyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)-3-methoxybenzonitrile,-   (42)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,7-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (43)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-8-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (44)    4-(2-acetyl-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)-3-methoxybenzonitrile,-   (45)    2-acetyl-5,6-dimethoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (46)    2-acetyl-1-(2,3-dihydro-1-benzofuran-7-yl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (47)    2-acetyl-5-methoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (48)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (49)    2-acetyl-6-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (50)    2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (51)    2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (52)    (+)-2-acetyl-1-(2-fluoro-6-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (53)    (+)-2-acetyl-1-(2-methoxy-4-methylphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (54)    (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (55)    (+)-2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (56)    (+)-2-acetyl-5,6-difluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],    or-   (57)    (+)-2-acetyl-5-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug    thereof,

[25] A pharmaceutical composition comprising the compound represented byformula (I) described in above [I], a salt thereof, an N-oxide thereof,a solvate thereof, or a prodrug thereof.

[26] The pharmaceutical composition according to above [25], which is anagent for preventing and/or treating a disease caused by stress,

[27] The pharmaceutical composition according to above [26], wherein thedisease caused by stress is a digestive system disease caused by stress,

[28] The pharmaceutical composition according to above [27], wherein thedigestive system disease caused by stress is irritable bowel syndrome,ulcerative colitis, or Crohn's disease,

[29] A pharmaceutical composition comprising the compound represented byformula (I) described in above [1], a salt thereof, an N-oxide thereof,a solvate thereof, or a prodrug thereof and one or more kind of agentsselected from an antianxiety, an antidepressant, an anticholinergic, agastrointestinal tract function regulator, a gastrointestinal tractprokinetic drug, an antidiarrheal, an evacuant, a calcium antagonist, aphosphodiesterase inhibitor and a serotonin antagonist in combination,

[30] A method for preventing and/or treating a disease caused by stressin a mammal comprising administering an effective amount of the compoundrepresented by formula (I) described in above [1], a salt thereof, anN-oxide, a solvate or a prodrug thereof to the mammal,

[31] Use of the compound represented by formula (I) according to above[1], a salt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof for preparing an agent for preventng and/or treating a diseasecaused by stress, and so on.

In the specification, a disease caused by stress is a general term of adisease developed by psychological or physical stressor and includes alldiseases known so called psychosomatic disorders. It includes,concretely, central nervous system diseases caused by stress,respiratory system diseases caused by stress, digestive system diseasescaused by stress, cardiovascular system diseases caused by stress,uropathy/reproductive system diseases caused by stress, gynecologicdiseases caused by stress, endocrine/metabolic diseases caused bystress, ophthalmologic diseases caused by stress, otolaryngologicaldiseases caused by stress, dental surgery/dentistry diseases caused bystress, surgical/orthopedic diseases caused by stress, skin diseasescaused by stress, other diseases caused by stress and so on. Itpreferably includes, central nervous system diseases caused by stress,respiratory system diseases caused by stress and/or digestive systemdiseases caused by stress. It more preferably includes digestive systemdiseases caused by stress.

In the specification, central nervous system diseases caused by stressinclude, for example, anxiety related disease, neurosis, panic disorder,sleep disorder, depression, reactive depression, epilepsy, Parkinson'sdisease, Perkinsonian syndrome, schizophrenia, autonomic dystonia,Huntington's disease, Alzheimer's disease, affective disorder, cognitivedisorder, migraine, tension headache, cluster headache, posttraumaticstress disorder (PTSD), dissociative disorder, insomnia, nervous cough,psychogenic convulsive seizure, psychogenic syncopal attack,maladjustment to job, burn-out syndrome, chronic fatigue syndrome,writer's cramp, spastic torticollis and so on. They preferably includeanxiety related disease, sleep disorder, depression and/or epilepsy.

In the specification, respiratory system diseases caused by stressinclude, for example, asthma, bronchial asthma, hyperventilationsyndrome, laryngeal spasm, chronic obstructive pulmonary diseases and soon. They preferably include asthma.

In the specification, digestive system diseases caused by stressinclude, for example, irritable bowel syndrome, peptic ulcer, functionaldyspepsia, gastric ulcer, duodenal ulcer, biliary tract dyskinesia,esophageal spasm, gastric atony, aerophagy, chronic gastritis, chronichepatitis, chronic panceatitis, eating disorder (e.g. neurogenicemaciation, anorexia, bulimia etc.), nervous (psychogenic) vomiting,nervous (psychogenic) nausea, inflammatory bowel disease (e.g.ulcerative colitis, Crohn's disease), abdominal tense syndrome,gastrointestinal neurosis (e.g. borborygmus-phobia etc.) and so on. Theypreferably include irritable bowel syndrome, ulcerative colitis, Crohn'sdisease.

In the specification, cardiovascular system diseases caused by stressinclude, for example, essential hypertension, arrhythmia, (neurological)angina pectoris, essential hypotension, orthostatic dysregulation,myocardial infarction, arteriosclerosis, vertigo and so on. Theypreferably include essential hypertension, arrhythmia and/or anginapectoris.

In the specification, uropathy/reproductive system diseases caused bystress include, for example, dysuria, nervous pollakisuria(hyperreflexic bladder), nocturia, enuresis, psychogenic ischuria,impotentia, prostatism, urethral syndrome and so on. They preferablyinclude dysuria.

In the specification, gynecologic disorder caused by stress include, forexample, menopausal disorder, menstrual pain, amenorrhea, menstrualdisorder, premenstrual syndrome, infertility, frigidity, seriousvomiting of pregnancy, abortion, immature birth, functional metrorrhagiaand so on.

In the specification, endocrine/metabolic diseases caused by stressinclude, for example, Bartter's syndrome, hyperthyroidism, glucosemetabolism disorder (e.g. diabetes, (reflex) hypoglycemia etc.), lipidmetabolism disorder (e.g. hyperlipidemia etc.), gout, osteoporosis,hypothalamus disease, pituitarium disease, parathyroid disease, adrenalcortex/adrenal medulla disease, gonadal disease, psychogenic polydipsia,adiposity and so on.

In the specification, ophthalmologic diseases caused by stress include,for example, asthenopia, central retinitis, floaters, blepharospasm,primary glaucoma, vertigo, eye hysteria and so on.

In the specification, otolaryngological diseases caused by stressinclude, for example, tinnitus, vertigo, psychogenic deafness, chronicsinusitis, allergic rhinitis, smell disorder, stuttering, anaudia,Meniere's disease, laryngopharynx discomfort, kinetosis, trachyphoniaand so on.

In the specification, dental surgery/dentistry diseases caused by stressinclude, for example, temporomandibular arthrosis, glossopharyngealneuralgia, sudden glossodynia, stomatitis, toothache, ozostomia,abnormal salivation, bruxism and so on.

In the specification, surgical/orthopedic diseases caused by stressinclude, for example, postoperative abdominal neurosis, dumpingsyndrome, polysurgery, plastic postoperative neurosis, rheumatoidarthritis, low back pain, cervico-omo-brachial syndrome, stiff neck,fibrositis, polyarthralgia, systemic myalgia, gout, spinal irritation,tic and so on.

In the specification, skin diseases caused by stress include, forexample, chronic urticaria, atopic dermatitis, hyperhidrosis, eczema,skin pruritus, alopecia greata and so on.

In the specification, other diseases caused by stress include, forexample, cancer, systemic lupus erythematosus and so on.

In the specification, anxiety related diseases include, for example,neurosis, generalized anxiety disorder (GAD), social-anxiety disorder(SAD), panic disorder, hyperactivity disorder, attention-deficit,personality disorder, bipolar disorder, autism and so on.

In the specification, cyclic group in “cyclic group which may have asubstituent(s)” represented by ring A² includes, for example,carbocyclic ring, heterocyclic ring and so on.

Said carbocyclic ring includes, for example, C3-20 mono-, bi-, tri- ortetra-aromatic carbocyclic ring partially or fully saturated,spiro-linked bi-, tri-, or tetra-carbocyclic ring, and bridged bi-,tri-, or tetra-carbocyclic ring and so on.

Said C3-20 mono-, bi-, tri- or tetra-aromatic carbocyclic ring partiallyor fully saturated means, for example, benzene, azulene, naphthalene,phenanthrene, anthracene, triphenylene, chrysene, naphthacene,pleiadene, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane,cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane,cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene,cyclohexadiene, cycloheptadiene, cyclooctadiene, pentalene,perhydropentalene, perhydroazulene, indene, perhydroindcnc, indane,dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene,heptalene, perhydroheptalene, biphenylene, as-indacene, s-indacene,acenaphthylene, acenaphtene, fluorene, phenalene, fluoranthene,acephenanthrylene, aceanthrylene, pyrene and so on.

Said spiro-linked bi-, tri-, or tetra-carbocyclic ring, and bridged bi-,tri-, or tetra-carbocyclic ring mean, for example, spiro[4.4]nonane,spiro[4.5]decane, spiro[5.5]undecane, bicyclo[2.2.1]heptane,bicyclo[2.2.1]hepta-2-ene, bicyclo[3.1.1]heptane,bicyclo[3.1.1]hepta-2-ene, bicyclo[2.2.2]octane,bicyclo[2.2.2]octa-2-ene, adamantane, noradamantane and so on.

Said heterocyclic ring includes, for example, 3-20 membered mono-, bi-,tri-, or tetra-aromatic heterocyclic ring optionally partially or fullysaturated containing 1 to 5 hetero atom(s) selected from oxygen,nitrogen and sulfur atom(s) and so on.

Said 3-20 membered mono-, bi-, tri-, or tetra-aromatic heterocyclic ringoptionally partially or fully saturated containing 1 to 5 hetero atom(s)selected from oxygen, nitrogen and sulfur atom(s) includes, for example,pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, pyrrolopyridine,benzoxazole, benzothiazole, benzimidazole, chromene, benzoxepine,benzoxazepine, benzoxadiazepine, benzothiepine, benzothiazepine,benzothiadiazepine, benzazepine, benzodiazepine, benzofurazan,benzothiadiazole, benzotriazole, carbazole, acridine, phenazine,dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine,phenoxathiin, thianthrene, phenanthridine, phenanthroline, perimidine,pyridonaphthyridine, pyrazoloisoquinoline, pyrazolonaphthyridine,pyrimidoindole, indolizinoindole, aziridine, azetidine, pyrroline,pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine,tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole,tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,tetrahydropyrrolopyridine, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnoline, benzoxathiane, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine,tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine,dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole,dihydroacridine, tetrahydroacridine, perhydroacridine,dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran,tetrahydrodibenzothiophene, perhydrodibenzofuran,perhydrodibenzothiophene, tetrapyridonaphthyridine,tetrahydro-β-carboline (e.g. 2,3,4,9-tetrahydro-1H-β-carboline etc.),tetrahydropyridopyrrolopyridine (e.g.6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine,2,3,4,9-tetrahydro-1H-pyrido[4′,3′:4,5]pyrrolo[2,3-c]pyridine,6,7,8,9-tetrahydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridine,6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine etc.),6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidine,dihydroazepinoindole, hexahydroazepinoindole (e.g.1,2,3,4,5,10-hexahydroazepino[3,4-b]indole,1,2,3,4,5,6-hexahydroazepino[4,3-b]indole etc.),tetrahydropyrazoloisoquinoline, tetrahydropyrazolonaphthyridine,dihydroazepinoindazole, hexahydroazepinoindazole,dihydropyrazolopyridoazepine, hexahydropyrazolopyridoazepine,tetrahydropyrimidoindole, dihydrothiazinoindole,tetrahydrothiazinoindole, dihydrooxazinoindole, tetrahydrooxazinoindole,hexahydroindolizinoindole, dihydroindolobenzdiazepine,octahydroindoloquinolizine, hexahydroimidazopyridoindole,hexahydropyrrolothiazepinoindole, dioxolane, dioxane, dithiolane,dithiane, dioxaindan, benzodioxane, chroman, benzodithiolane,benzodithiane, azaspiro[4.4]nonane, oxazaspiro[4.4]nonane,oxazaspiro[2.5]octane, dioxaspiro[4.4]nonane, azaspiro[4.5]decane,thiaspiro[4.5]decane, clithiaspiro[4.5]decane, dioxaspiro[4.5]decane,oxazaspiro[4.5]decane, azaspiro[5.5]undecane, oxaspiro[5.5]undecane,dioxaspiro[5.5]undecane,2,3,4,9-tetrahydrospiro[β-carboline-1,1′-cyclopentane],1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],1,2,4,9-tetrahydrospiro[β-carboline-3,1′-cyclopropane],1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclobutane],1,2,4,9-tetrahydrospiro[β-carboline-3,1′-cyclobutane],1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopentane],1,2,4,9-tetrahydrospiro[β-carboline-3,1′-cyclopentane],azabicyclo[2.2.1]heptane, oxabicyclo[2.2.1]heptane,azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane,oxabicyclo[3.2.1]octane, azabicyclo[2.2.2]octane,diazabicyclo[2.2.2]octane, 1,3-benzodioxol and so on.

In the specification, substituent in “cyclic group which may have asubstituent(s)” represented by A² includes, for example, (1) hydrocarbonwhich may have a substituent(s), (2) carbocyclic ring which may have asubstituent(s), (3) heterocyclic ring which may have a substituent(s),(4) hydroxyl which may have a substituent(s), (5) mercapto which mayhave a substituent(s), (6) amino which may have a substituent(s), (7)carbamoyl which may have a substituent(s), (8) sulfamoyl which may havea substituent(s), (9) carboxyl, (10) alkoxycarbonyl (e.g. C1-6alkoxycarbonyl etc., such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and so on),(11) sulfo (—SO₃H), (12) sulfino (—SO₂H), (13) phosphono (—P(═O)OH₂),(14) nitro, (15) cyano, (16) amidino, (17) imino, (18) dihydroborono(—B(OH)₂), (19) halogen atom (e.g. fluorine, chlorine, bromine, iodine),(20) alkylsufinyl (e.g. C1-4 alkylsulfinyl etc., such as methylsulfonyl,ethylsulfinyl and so on), (21) aromatic ring sulfinyl (e.g. C6-10aromatic ring sulfinyl etc., such as phenylsulfinyl and so on), (22)alkylsulfonyl (e.g. C1-4 alkylsulfonyl etc., such as methylsulfonyl,ethylsulfonyl and so on), (23) aromatic ring sulfonyl (e.g. C6-10aromatic ring sulfonyl etc., phenylsulfonyl and so on), (24) oxo, (25)thioxo, (26) (C1-6 alkoxyimino)methyl (e.g. (methoxyimino)methyl etc.),(27) acyl (28) formyl, (29) alkyl substituted with hydroxyl which mayhave a substituent(s), (30) alkyl substituted with mercapto which mayhave a substituent(s), (31) alkyl substituted with amino which may havea substituent(s), (32) (alkyl which may have asubstituent(s))oxycarbonyl, (33) tri(C1-6 alkyl)silyl (e.g.trimethylsilyl etc.) and so on. These optional substituents may besubstituted 1-5 at the replaceable position.

Hydrocarbon in “(1) hydrocarbon which may have a substituent(s)”includes, for example, alkyl, alkenyl, alkynyl, alkylidene, alkenylideneand so on.

Alkyl includes, for example, straight-chain or branched-chain C1-20alkyl and so on, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, hexyl, heptyl,octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl etc. Straight-chainor branched-chain C1-8 alkyl is preferred. Straight-chain orbranched-chain C1-6 alkyl is more preferred.

Alkenyl includes, for example, straight-chain or branched-chain C2-8alkenyl and so on, such as ethenyl, propenyl, butenyl, pentenyl,hexenyl, heptenyl, octenyl etc. Straight-chain or branched-chain C2-6alkenyl is preferred.

Alkynyl includes, for example, straight-chain or branched-chain C2-8alkynyl and so on, such as ethynyl, propynyl, butynyl, pentynyl,hexynyl, heptynyl, octynyl etc. Straight-chain or branched-chain C2-6alkynyl is preferred.

Alkylidene includes, for example, straight-chain or branched-chain C1-8alkylidene and so on, such as methylidene, ethylidene, propylidene,butylidene, pentylidene, hexylidene, heptylidene, octylidene etc.

Alkenylidene includes, for example, straight-chain or branched-chainC2-8 alkenylidene and so on, such as ethenylidene, propenylidene,butenylidene, pentenylidene, hexenylidene, heptenylidene, octenylideneetc.

Here, substituent of hydrocarbon includes, for example, hydroxyl,mercapto, amino, carboxyl, nitro, cyano, mono- or di-C1-6 alkylamino(e.g. methylamino, ethylamino, propylamino, dimethylamino, diethylaminoetc.), N-aromatic ring amino (e.g. N-phenylamino etc.), N-aromaticring-N-alkylamino (e.g. N-phenyl-N-methylamino, N-phenyl-N-ethylamino,N-phenyl-N-propylamino, N-phenyl-N-butylamino, N-phenyl-N-pentylamino,N-phenyl-N-hexylamino etc.), acylamino, N-acyl-N-alkylamino, C1-6 alkoxy(e.g. methoxy, ethoxy, propoxy, isopropoxy, hexyloxy etc.), C3-7cycloalkyl-C1-6 alkoxy (e.g. cyclohexylmethyloxy, cylcopentylethyloxyetc.), C3-7 cycloalkyloxy (e.g. cylcohexyloxy etc.), C7-15 aralkyloxy(e.g. benzyloxy, phenethyloxy, phenylpropyloxy, naphthylmethyloxy,naphthylethyloxy etc.), phenoxy, C1-6 alkoxycarbonyl (e.g.methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl etc.), C1-6alkylcarbonyloxy (e.g. acetoxy, ethylcarbonyloxy etc.), C1-6 alkylthio(e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio,hexylthio etc.), halogen atom (e.g. florine, chlorine, bromine, iodine),alkylsulfonyl (e.g. C1-4 alkylsulfonyl etc., such as methylsulfonyl,ethylsulfonyl and so on), aromatic ring sulfonyl (e.g. C6-10 aromaticring sulfonyl etc., such as phenylsulfonyl and so on), carbamoyl whichmay have a substituent(s) (e.g. carbamoyl without substituent,N-mono-C1-6 alkylcarbamoyl (e.g. N-methylcarbamoyl, N-ethykarbamoyl,N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl etc.), N,N-diC1-6 alkylcarbamoyl (e.g. N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl etc.),piperidine-1-ylcarbonyl etc.), acyl, carbocyclic ring which may have asubstituent(s), and heterocyclic ring which may have a substituent(s)etc. These optional substituents may be substituted 1-4 at thereplaceable position. Here, allyl in N-acyl-N-alkylamino means, forexample, straight-chain or branched-chain C1-6 alkyl and so on, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc. In addition, acyl in acyl, acylamino andN-acyl-N-alkylamino has the same meanings as that of the after-mentioned(27) acyl. Additionally, carbocylic ring which may have a substituent(s)and heterocyclic ring which may have a substituent(s) have the samemeanings as that of the after-mentioned (2) carbocyclic ring which mayhave a substituent(s), and (3) heterocyclic ring which may have asubstituent(s).

Carbocylcic ring in “(2) carbocyclic ring which may have asubstituent(s)” has the same meanings as that of carbocyclic ringrepresented by the above described ring A². Here, substituent ofcarbocyclic ring includes, for example, straight-chain or branched-chainC1-8 alkyl optionally with hydroxyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl,heptyl, octyl etc.), straight-chain or branched-chain C2-6 alkenyl (e.g.ethenyl, propenyl, butenyl, pentenyl, hexenyl etc.), straight-chain orbranched-chain C2-6 alkynyl (e.g. ethynyl, propynyl, butynyl, pentynyl,hexynyl etc.), hydroxyl, straight-chain or branched-chain C1-6 alkoxy(e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy,tert-butoxy, pentyloxy, hexyloxy etc.), mercapto, straight-chain orbranched-chain C1-6 alkylthio (e.g. methylthio, ethylthio, propylthio,isopropythio, butylthio, isobutylthio, tert-butylthio, pentylthio,hexylthio etc.), amino, mono- or di-C1-6 allylamino (e.g. methylamino,ethylamino, propylamino, isopropylamino, butylamino, isobutylamino,tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino,dipropylamino, N-methyl-N-ethylamino etc.), halogen atom (e.g. fluorine,chlorine, bromine, iodine), cyano, nitro, carboxyl, straight-chain orbranched-chain C1-6 alkoxycarbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl etc.), straight-chain orbranched-chain C1-6 alkylcarbonyloxy (e.g. acetoxy, ethylcarbonyloxyetc.), trihalomethyl (e.g. tirfluoromethyl etc.), trihalomethoxy (e.g.trifluoromethoxy etc.), trihalomethylthio (e.g. trifluoromethylthioetc.), dihalomethylthio (e.g. difluoromethylthio etc.), oxo, carbocylicring (it has the same meanings as that of carbocyclic ring representedby the above described ring A²), heterocyclic ring (it has the samemeanings as that of heterocyclic ring represented by the above describedring A²) and so on. These optional substituents may be substituted 1-4at the replaceable position.

Heterocyclic ring in “(3) heterocyclic ring which may have asubstituent(s)” has the same meanings as that of heterocyclic ringrepresented by the above described ring A². Here, substituent ofheterocyclic ring has the same meanings as that of substituent in theabove described “(2) carbocyclic ring which may have a substituent(s)”.

Substituent in “(4) hydroxyl which may have a substituent(s)”, “(5)mercapto which may have a substituent(s)” and “(6) amino which may havea substituent(s)” include, for example, hydrocarbon which may have asubstituent(s) (it has the same meanings as that of the above described“(1) hydrocarbon which may have a substituent(s)”), carbocyclic ringwhich may have a substituent(s) (it has the same meanings as that of theabove described “(2) carbocyclic ring which may have a substituent(s)”),heterocyclic ring which may have a substituent(s) (it has the samemeanings as that of the above described “(3) heterocyclic ring which mayhave a substituent(s)”), allylsulfonyl (e.g. C1-4 alkylsulfonyl etc.,such as methylsulfonyl, ethylsulfonyl and so on), aromatic ring sulfonyl(e.g. C6-10 aromatic ring sulfonyl etc., such as phenylsulfonyl and soon), acyl (it has the same meanings as that of the after described (27)acyl), (alkyl which may have a substituent(s)) oxycarbonyl (it has thesame meanings as that of the after described “(32) (alkyl which may havea substituent(s)) oxycarbonyl”) and so on.

Here, “(4) hydroxyl which may have a substituent(s)” includes, forexample, C1-8 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy,octyloxy etc.), hydroxy substituted with carbocyclic ring which may havea substituent(s) (e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy, cyclooctyloxy etc.) and so on.

“(7) Carbamoyl which may have a substituent(s)” includes, for example,carbamoyl without substituent, N-mono-C1-6 alkylcarbamoyl (e.g.N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl etc.), N,N-di C1-6 alkylcarbamoyl(e.g. N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl etc.),piperidine-1-ylcarbonyl and so on.

“(8) Sulfamoyl which may have a substituent(s)” includes, for example,sulfamoyl without substituent, N-mono-C1-6 alkylsulfamoyl (e.g.N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl,N-isopropylsulfamoyl, N-butylsulfamoyl etc.), N,N-di C1-6 alkylsulfamoyl(e.g. N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,N,N-dipropylsulfamoyl, N,N-dibutylsulfamoyl etc.) and so on.

“(27) Acyl” includes, for example, alkylcarbonyl which may have asubstituent(s) (wherein, alkyl which may have a substituent(s) has thesame meanings as that of alkyl which may have a substituent(s) in theabove described “(1) hydrocarbon which may have a substituent(s)”),alkenylcarbonyl which may have a substituent(s) (wherein, alkenyl whichmay have a substituent(s) has the same meanings as that of alkenyl whichmay have a substituent(s) in the above described “(1) hydrocarbon whichmay have a substituent(s)”), alkynylcarbonyl which may have asubstituent(s) (wherein, alkynyl which may have a substituent(s) has thesame meanings as that of alkynyl which may have a substituent(s) in theabove described “(1) hydrocarbon which may have a substituent(s)”),carbocyclic ring carbonyl which may have a substituent(s) (wherein,carbocyclic ring which may have a substituent(s) has the same meaningsas that of the above described “(2) carbocyclic ring which may have asubstituent(s)”), heterocyclic ring carbonyl which may have asubstituent(s) (wherein, heterocyclic ring which may have asubstituent(s) has the same meanings as that of the above described “(3)heterocyclic ring which may have a substituent(s)”) and so on.

Hydroxyl which may have a substituent(s) in “(29) alkyl substituted withhydroxyl which may have a substituent(s)” has the same meanings as thatof the above described “(4) hydroxyl which may have a substituent(s)”.Mercapto which may have a substituent(s) in “(30) alkyl substituted withmercapto which may have a substituent(s)” has the same meanings as thatof the above described “(5) mercapto which may have a substituent(s)”.Amino which may have a substituent(s) in “(31) alkyl substituted withamino which may have a substituent(s)” has the same meanings as that ofthe above described “(6) amino which may have a substituent(s)”. Inaddition, alkyl in “(29) alkyl substituted with hydroxyl which may havea substituent(s)”, “(30) alkyl substituted with mercapto which may havea substituent(s) and “(31) alkyl substituted with amino which may have asubstituent(s)” includes, for example straight-chain or branched-chainC1-6 alkyl and so on, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.

Alkyl which may have a substituent(s) in “(32) (alkyl which may have asubstituent(s)) oxycarbonyl” has the same meanings as that of “alkylwhich may have a substituent(s)” in “(1) hydrocarbon which may have asubstituent(s)”.

In the specification, “hydrocarbon which may have a substituent(s)”represented by B has the same meanings as that of “(1) hydrocarbon whichmay have a substituent(s)” in substituent of “cyclic group which mayhave a substituent(s)” represented by ring A².

In the specification, “cyclic group which may have a substituent(s)”represented by B has the same meanings as that of “cyclic group whichmay have a substituent(s)” represented by ring A².

In the specification, “substituent” represented by R¹, R², R³, R⁴, R⁵,R⁶, R⁷ or R⁸ has the same meanings as that of “cyclic group” in “cyclicgroup which may have a substituent(s)” represented by ring A².

In the specification, “substituent” in “cyclic group which may have asubstituent(s)” formed by two R¹ taken together, and “cyclic group whichmay have a substituent(s)” formed by R⁴ and R⁵ and/or R⁶ and R⁷ takentogether with their binding carbon atoms, has the same meanings as thatof substituent in “cyclic group which may have a substituent(s)”represented by ring A².

In the specification, “cyclic group” in “cyclic group which may have asubstituent(s)” formed by two R¹ taken together, and “cyclic group whichmay have a substituent(s)” formed by R⁴ and R⁵ and/or R⁶ and R⁷ takentogether with their binding carbon atoms, includes, for example, C3-10mono-aromatic carbocyclic ring, which is partially or fully saturated,3-10 membered mono-aromatic heterocyclic ring which may be partially orfully saturated, which may contain 1 to 2 hetero atom(s) selected fromoxygen atom, nitrogen atom and sulfur atom(s) and so on.

Said C3-10 mono-aromatic carbocyclic ring, which is partially or fullysaturated includes, for example, cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane,cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene,cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclootadiene ring andso on.

Said 3-10 membered mono-aromatic heterocyclic ring which may bepartially or fully saturated, which may contain 1 to 4 hetero atom(s)selected from oxygen atom, nitrogen atom and sulfur atom(s) includes,for example, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,imidazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodizepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrotiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisooxazole, tetrahydroisooxazole (isooxazolidine),dihydrothiazole, tetrahydrothiazole (isothiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrothiazine, tetrahydrothiazine,dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, morpholine,thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane ringand so on.

“Mono-carbocyclic ring” represented by ring A¹ includes, for example,C3-10 mono-aromatic carbocyclic ring, which is partially or fullysaturated and so on. Said C3-10 mono-aromatic carbocyclic ring, which ispartially or fully saturated includes, for example, cyclopropene,cyclobutene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene,cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene ring and so on.

“Mono-heterocyclic ring” represented by ring A¹ includes, for example,3-10 membered mono-aromatic heterocyclic ring which may be partially orfully saturated, which may contain 1 to 5 hetero atom(s) selected fromoxygen atom, nitrogen atom and sulfur atom(s) and so on. Said 3-10membered mono-aromatic heterocyclic ring which may be partially or fullysaturated, which may contain 1 to 5 hetero atom(s) selected from oxygenatom, nitrogen atom and sulfur atom(s) includes, for example, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiopyran, thiepine, oxazole, isooxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, aziridine, azetidine, pyrroline, pyrrolidine,imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline,tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodizepine, perhyclrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrotiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisooxazole, tetrahydroisooxazole (isooxazolidine),dihydrothiazole, tetrahydrothiazole (triazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, tetrahydrothiadiazine,dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine,morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane,dithiane ring and so on.

In the specification, C1-3 alkylene in “C1-3 alkylene which may have asubstituent(s)” repredented by X or Z includes, for example, methylene,ethylene, propylene and so on.

In the specification, C2-3 alkenylne in “C2-3 alkenylene which may havea substituent(s)” repredented by X or Z includes, for example,ethenylene, propenylene and so on.

In the specification, C2-3 alkynylene in “C2-3 alkynylene which may havea substituent(s)” repredented by X or Z includes, for example,ethynylene, propynylene and so on.

In the specification, “substituent” in “C1-3 alkylene which may have asubstituent(s)”, “C2-3 alkenylene which may have a substituent(s)” or“C2-3 alkynylene which may have a substituent(s)” has the same meaningsas that of substituent in “cyclic group which may have a substituent(s)”represented by ring A². These optional substituents may be substituted1-2 at the replaceable position.

Ring A¹ preferably includes, benzene, pyridine, pyrimidine, pyrazinering and so on. X preferably includes, bond, C1-3 alkylene which mayhave a substituent(s), C2-3 alkenylene which may have a substituent(s),C2-3 alkynylene which may have a substituent(s). It more preferablyincludes, bond, C1-3 alkylene which may have a substituent(s). Itparticularly preferably includes bond.

Y preferably includes, —C(═O)—, —C(═S)—, —C(═O)NR⁸—, —SO₂—, —C(═O)O— or—SO₂NR⁸— group (proviso that a left side of each group binds to X). Itmore preferably includes, —C(═O)—, —C(═S)—, —C(═O)NR⁸— or —C(═O)O—group. It particularly preferably includes —C(═O)— or —C(═O)NR⁸— group.

Z preferably includes, bond, C1-3 alkylene which may have asubstituent(s), C2-3 alkenylene which may have a substituent(s), C2-3alkynylene which may have a substituent(s). It more preferably includes,bond, C1-3 alkylene which may have a substituent(s).

“Hydrocarbon which may have a substituent(s)” represented by Bpreferably includes, C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl which maybe substituted by 1 to 4 substituent(s) arbitrarily selected fromhydroxyl, mercapto, amino, carboxyl, nitro, cyano, mono- or di-C1-6alkylamino, C1-6 alkoxy, C1-6 alkylcarbonyloxy, C1-6 alkylthio, halogenatom, acyl, carbocylic ring which may have a substituent(s), andheterocyclic ring which may have a substituent(s). It more preferablyincludes, C1-8 alkyl which may be substituted by 1 to 4 substituent(s)arbitrarily selected from carbocyclic ring which may have asubstituent(s), and heterocyclic ring which may have a substituent(s).

“Cyclic group which may have a substituent(s)” represented by B or ringA² preferably includes, C3-10 mono- or bi-aromatic carbocyclic ringpartially or fully saturated (e.g. benzene, cyclopentane, naphthalene,adamantane etc.), or 3-10 membered mono or bi-aromatic heterocyclic ringwhich may be partially or fully saturated, which may contain 1 to 4hetero atom(s) selected from oxygen atom, nitrogen atom and sulfuratom(s) (e.g. pyridine, thiophene, tetrahydropyran, dihydrobenzofuran,1,3-benzodioxol etc.) which may be substituted by 1 to 4 substituent(s)arbitrarily selected from C1-8 alkyl, C1-8 alkyl which may have asubstituent(s), C2-8 alkenyl, C2-8 alkynyl, carbocyclic ring,heterocyclic ring, hydroxyl, C1-8 alkoxy (e.g. methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,hexyloxy, heptyloxy, octyloxy etc.), C1-8 alkoxy which may have asubstituent(s), C3-7 cycloalkyloxy (e.g. cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy etc.), C3-7 cycloalkyloxywhich may have a substituent(s), mercapto, C1-8 alkylthio (e.g.methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio,heptylthio, octylthio etc.), amino, NR¹⁰¹R¹⁰² (wherein, R¹⁰¹ and R¹⁰²are each independently hydrogen atom, or C1-8 alkyl), carboxyl, C1-6alkoxycarbonyl, nitro, ciano, halogen atom, oxo, acyl, formyl andtri(C1-6 alkyl) silyl etc.

“Cyclic group which may have a substituent(s)” represented by ring A² ispreferably substituted by at least two same or different substituents.In addition, said at least two same or different substituents may betaken together with their binding atoms to form cyclic group (thiscyclic group has the same meanings as that of “cyclic group” in theabove described “cyclic group which may have a substituent(s)” which twoR¹ are taken together to form, “cyclic group which may have asubstituent(s)” which R⁴ and R⁵ and/or R⁶ and R⁷ are taken together withtheir binding carbon atoms to form. It includes, for example, furan,pyran, oxazole, isoxazole, oxazine, dihydrofuran, tetrahydrofuran,dihydropyran, tetrahydropyran, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrooxazine, tetrahydrooxazine, morpholine, oxathiane, dioxolane,dioxane ring etc.). Ring A² is more preferably substituted by two sameor different substituents.

Said two same or different substituents preferably includes, forexample, (1) halogen atom (e.g. fluorine, chlorine, bromine, iodine),(2) cyano, (3) C1-8 alkyl which may have a substituent(s) (it has thesame meanings as the described above), (4) C1-8 alkoxy which may have asubstituent(s) (it has the same meanings as the described above), (5)C3-7 cycloalkyloxy which may have a substituent(s) (it has the samemeanings as the described above) and the like. Here, “substituent” in“C1-8 alkyl which may have a substituent(s)”, “C1-8 alkoxy which mayhave a substituent(s)” or “C3-7 cycloalkyloxy which may have asubstituent(s)” includes, for example, C1-8 alkyl, C2-8 alkenyl, C2-8alkynyl, carbocylic ring, heterocyclic ring, hydroxyl, C1-8 alkoxy,mercapto, C1-8 alkylthio, amino, NR¹⁰¹R¹⁰² (wherein, R¹⁰¹ and R¹⁰² areeach independently hydrogen atom or C1-8 alkyl), carboxyl, C1-6alkoxycarbonyl, nitro, cyano, halogen atom, oxo, acyl, formyl, tri(C1-6alkyl) silyl and the like. These optional substituents may besubstituted 1-9 at the replaceable position. It preferably includeshalogen atom and the like. It more preferably includes fluorin atom.Here, “C1-8 alkoxy” in “C1-8 alkoxy which may have a substituent(s)”preferably includes methoxy, isopropoxy and the like. “C3-7cycloalkyloxy which may have a substituent(s)” preferably includescyclopentyloxy and the like. Said two same or different substituentsmore preferably includes, for example, (1) fluorine atom, (2) chlorineatom, (3) cyano, (4) methyl, (5) methoxy, (6) isopropoxy, (7)cyclopentyloxy and the like. One substituent among said two same ordifferent substituents preferably includes C1-8 alkoxy which may have asubstituent(s) or C3-7 cycloalkyloxy which may have a substituent(s). Itparticularly preferably includes methoxy, isopropoxy, cyclopentyloxy.

In addition, when

(wherein all the symbols have the same meanings as the described above)is a cyclic group which has at least two same or different substituents,one substituent of said two same or different substituents is preferablysubstituted to an atom neighboring D. Such a substituent preferablyincludes, for example, C1-8 alkoxy which may have a substituent(s) orC3-7 cycloalkyloxy which may have a substituent(s) and the like.

“Cyclic group” represented by

preferably includes, benzene, thiophene, cyclopentane, ortetrahydropyran and the like. It more preferably includes benzene andthe like. It further preferably includes

(wherein, R²⁰¹ is C1-8 alkoxy which may have a substituent(s) or C3-7cycloalkyloxy which may have a substituent(s), R²⁰² is halogen atom,cyano, C1-8 alkyl which may have a substituent(s) or C1-8 alkoxy whichmay have a substituent(s)) and the like. R²⁰¹ is more preferably thesubstituent selected from (1) methoxy which may be substituted byfluorine atom, (2) isopropoxy which may be substituted by fluorine atomand (3) cyclopropyloxy which may be substituted by fluorine atom. R²⁰²is more preferably one substituent selected from (1) fluorine atom, (2)chlorine atom, (3) cyano, (4) methyl and (5) methoxy. R²⁰¹ isparticularly preferably methoxy which may be substituted by fluorineatom.

In addition, when R²⁰¹ and R²⁰² are taken together with their bindingatom to form cyclic group, “cyclic group” represented by

(wherein, all the symbols have the same meanings as the described above)preferably includes the ring represented by

(wherein

is 5-6 membered mono-heterocyclic ring which may further include onehetero atom selected from oxygen atom, nitrogen atom and sulfur atom)and the like. Here, 5-6 membered mono-heterocyclic ring which mayfurther include one hetero atom selected from oxygen atom, nitrogen atomand sulfur atom includes, for example, furan, pyran, oxazole, isoxazole,oxazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole,tetrahydroisoxazole (isoxazolidine), dihydrooxazine, tetrahydrooxazine,morpholine, oxathiane, dioxolane, dioxane and the like.

“Substituent” represented by R¹, R², R³, R⁴, R⁵, R⁶ or R⁷ preferablyincludes C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, carbocyclic ring,heterocyclic ring, hydroxyl, C1-8 alkoxy, mercapto, C1-8 alkylthio,amino, NR¹⁰¹R¹⁰² (wherein R¹⁰¹ and R¹⁰² are each independently hydrogenatom or C1-8 alkyl), carboxyl, C1-6 alkoxycarbonyl, nitro, cyano,halogen atom, oxo, acyl, formyl, tri(C1-6 alkyl) silyl and the like.

“Cyclic group which may have a substituent(s)” which R⁴ and R⁵ and/or R⁶and R⁷ are taken together with their binding carbon atoms to represent,preferably includes C3-8 cycloalkyl (e.g. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.) which may besubstituted by 1 to 4 substituent(s) selected from C1-8 alkyl, C2-8alkenyl, C2-8 allynyl, carbocyclic ring, heterocyclic ring, hydroxyl,C1-8 alkoxy, mercapto, C1-8 alkylthio, amino, NR¹⁰¹R¹⁰² (wherein R¹⁰¹and R¹⁰² are each independently hydrogen atom or C1-8 alkyl), carboxyl,C1-6 alkoxycarbonyl, nitro, cyano, halogen atom, oxo, acyl, formyl,tri(C1-6 alkyl) silyl and the like.

R⁴ and R⁵ are preferably taken together their binding carbon atoms toform cyclic group which may have a substituent(s). Such a cyclic grouppreferably includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andthe like. It more preferably includes cyclopropyl and the like.

In the specificaition, D is preferably a carbon atom and the like.

In the specification, “C1-8 alkyl which may have a substituent(s)”represented by B² has the same meanings as that of “C1-8 alkyl which mayhave a substituent(s)” represented by B. It is preferably C1-8 alkylwithout substituent and the like. It is more preferably methyl and thelike.

In the specification, “C1-8 alkoxy which may have a substituent(s)” or“C3-7 cycloalkyloxy which may have a substituent(s)” represented by R²⁰¹has the same meanings as that of “C1-8 alkoxy which may have asubstituent(s)” or “C3-7 cycloalkyloxy which may have a substituent(s)”in “two same or different substituents” among the above described ringA², respectively. “Halogen atom”, “C1-8 alkyl which may have asubstituent(s)” or “C1-8 alkoxy which may have a substituent(s)”represented by R²⁰² has the same meanings as that of “halogen atom”,“C1-8 alkyl which may have a substituent(s)” or “C1-8 alkoxy which mayhave a substituent(s)” in “two same or different substituents” among theabove described ring A², respectively.

The compound represented by formula (I) preferably includes the compoundrepresented by formula (I-A):

(wherein, all the symbols have the same meanings as the describedabove), or the compound represented by formula (I-B):

(wherein, all the symbols have the same meanings as the describedabove).

The compound represented by formula (I-A) preferably includes thecompound represented by formula (I-A-1):

(wherein, R^(1A) has the same meanings as that of R¹, tB is 0 or aninteger of 1 to 3, the other symbols have the same meanings as thedescribed above).

The compound represented by formula (I-B) preferably includes thecompound represented by formula (I-B-1)

(wherein, to is 0 or an integer of 1 to 4, R⁴ and R⁵ are taken togetherwith their binding carbon atom to form cyclic group which may have asubstituent(s), the other symbols have the same meanings as thedescribed above), the compound represented by formula (I-B-2)

(wherein, all the symbols have the same meanings as the describedabove), the compound represented by formula (I-B-3)

(wherein, all the symbols have the same meanings as the describedabove), the compound represented by formula (I-B-4)

(wherein, all the symbols have the same meanings as the describedabove), or the compound represented by formula (I-B-5)

(wherein, all the symbols have the same meanings as the describedabove).

In addition, among the compound represented by formula (I-B-1), itpreferably includes the compound of which ring A² is a cyclic grouphaving at least two same or different substituents. Concretely, itpreferably includes the compound represented by formula (I-B-1-1)

(wherein, all the symbols have the same meanings as the describedabove).

It particularly preferably includes the compound represented by formula(I-B-1-2)

(wherein, all the symbols have the same meanings as the describedabove).

Additionally, among the compound represented by formula (I), both thecompound represented by formula (I-C)

(wherein, all the symbols have the same meanings as the described above)and the compound represented by formula (I-D)

(wherein, all the symbols have the same meanings as the described above)are preferred. It particularly preferably includes the compoundrepresented by formula (I-C).

In addition, in case of the compound represented by formula (I-B-1-1) orformula (I-B-1-2), it preferably includes ring A² is β-configuration.Concretely, it preferably includes the compound represented by formula(I-B-1-1-a)

(wherein, all the symbols have the same meanings as the describedabove). It particularly preferably includes the compound represented byformula (I-B-1-2-a)

(wherein, all the symbols have the same meanings as the describedabove).

Preferable compounds for preparing the pharmaceutical composition whichis a preventive and/or therapeutic agent for the diseases caused bystress include all the compounds of the present invention showed inExamples. Particularly preferable compounds include, for example,

-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carbonline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-rnethoxyphenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-5-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-5-chloro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-5-fluoro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-6-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(5-fluoro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-fluoro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(2,4-dimethoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(2-fluoro-6-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-5-fluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-fluoro-2-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-6-methoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(2-fluoro-6-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-6,7-dimethoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(2-methoxy-4-methylphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(2,3-dihydro-1-benzofuran-7-yl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (1S)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (+)-2-acetyl-1-(2-fluoro-6-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (+)-2-acetyl-5-fluoro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-5-chloro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-5,6-difluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-5,6-difluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-5-chloro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-isopropoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-[4-chloro-2-(cyclopentyloxy)phenyl]-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   4-(2-acetyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)-3-methoxybenzonitrile,-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,7-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-8-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   4-(2-acetyl-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)-3-methoxybenzonitrile,-   2-acetyl-5,6-dimethoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-5-methoxy-1-(2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   4-(2-acetyl-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)benzonitrile,-   2-acetyl-1-(2,3-dihydro-1-benzofuran-7-yl)-5-methoxy-1,2,3,9-tetrahydrospiro[j3-carboline-4,1′-cyclopropane],-   2-acetyl-5-methoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-6-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (+)-2-acetyl-1-(2-fluoro-6-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (+)-2-acetyl-1-(2-methoxy-4-methylphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (+)-2-acetyl-1-(4-chloro-2-methoxylphenyl)-6-methoxy-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],-   (+)-2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carb    cline-4,1′-cyclopropane],-   (+)-2-acetyl-5,6-difluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cylcopropane],-   (+)-2-acetyl-5-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and the like.    [Isomer]

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkenyl, alkynyl, alkoxy, allylthio,alkylene, alkenylene, alkynylene group include straight-chain orbranched-chain ones. In addition, isomers on double bond, ring, fusedring (E-, Z-, cis-, trans-isomer), isomers generated from asymmetriccarbon atom(s) (R-, S-isomer, α-, β-configuration, enantiomer,diastereomer), optically active isomers having optical activity (D-, L-,d-, 1-isomer), polar compounds generated by chromatographic separation(more polar compound, less polar compound), equilibrium compounds,rotational isomers, mixtures thereof at voluntary ratios and racemicmixtures are also included in the present invention.

According to the present invention, unless otherwise indicated and as isapparent for those skilled in the art,

the symbol

indicates that it is bound to α-configuration,

the symbol

indicates that it is bound to β-configuration,

and the

indicates that it is a mixture of α-configuration and β-configurationwhich may be mixed by optional ratio.

The optically active compounds of the present invention may not onlyinclude 100% pure ones but also the other optical isomers less than 50%.

[Salt, N-Oxide and Solvent]

The salts of the compounds represented by formula (I) include all ofpharmaceutically acceptable ones. As pharmaceutically acceptable salts,non-toxic, water-soluble salts are preferred. The suitable salts includefor example, salts of alkali metals (e.g., potassium, sodium, lithium,etc.), salts of alkaline earth metals (e.g., calcium, magnesium, etc.),ammonium salts (e.g., tetramethylammonium salt, tetrabutylammonium salt,etc.), pharmaceutical acceptable salts of organic amine (e.g.,triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine,N-methyl-D-glucamine, etc.), acid addition salts (salts of inorganicacids (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate,phosphate, nitrate etc.), and salts of organic acids (e.g., acetate,trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate,benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, isethionate, glucuronate, gluconate etc.).

N-oxide of the compound represented by formula (I) means nitrogen atomof the compound represented by formula (I) is oxidized. The N-oxide ofthe compound of the present invention may be the above described saltsof alkali (earth) metals, ammonium salts, salts of organic amine, acidaddition salts and so on.

The suitable solvates of the compound represented by formula (I) includefor example, hydrates, solvates of the alcohols (e.g., ethanol etc.),and so on. The solvates are preferably nontoxic and water-soluble. Inaddition, the solvate of compound of the present invention included theabove described salts of alkali (earth) metals, ammonium salts, salts oforganic amine, acid addition salts, N-oxide and so on.

The compound of the present invention may be converted into the abovedescribed N-oxide, the above described solvates by known methods.

[Prodrug]

The prodrug of the compounds represented by formula (I) means a compoundis the compound represented by formula (I) by reaction with enzymes,gastric acids and so on within an organism. The prodrug of the compoundsrepresented by formula (I) include, when the compounds represented byformula (I) have amino, the prodrug is the compounds the amino of whichis acylated, alkylated, phosphorylated (e.g., the compounds are that theamino of the compounds represented by formula (I) is eicosanoated,alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylated,tetrahydrofuranated, pyrrolidylmethylated, pivaloyloxymethylated,acetoxymethylated, tert-butylated, etc.); when the compounds representedby formula (I) have hydroxyl, the prodrug is the compounds the hydroxylof which are acylated, alkylated, phosphorylated, borated (e.g., thecompounds are that the hydroxyl of the compounds represented by formula(I) are acetylated, palmitoylated, propanoylated, pivaloylated,succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylatedetc.); when the compounds represented by formula (I) have carboxyl, theprodrug is the compound the carboxyl of which are esterified, amidated(e.g., the compounds are that the carboxyl of the compounds representedby formula (I) is ethylesterified, phenylesterified,carboxymethylesterified, dimethylaminomethylesterified,pivaloyloxymethylesterified, ethoxycarbonyloxyethylesterified,phthalidylesterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterified,cyclohexyloxycarbonylethylesterified, methylamidated etc.); and so on.These compounds can be prepared by known methods. In addition, theprodrug of the compound represented by formula (I) may be either hydrateor non-hydrate. In addition, the prodrug of the compound represented byformula (I) may be converted into the compound represented by formula(I) under the physiological condition which is described in “thedevelopment of medicine” vol. 7 “molecular design” published in 1991Hirokawa shoten p.p. 163-198. Further, the compound represented byformula (I) may be labeled with isotopes (e.g. ³H, ¹⁴C, ³⁵S, ¹²⁵I etc.)and so on.

[Pharmacological Activity]

As pharmacological test except one described in Example, for examplethere are the methods as follows.

Determination of Pregnenolone in Rat Adrenocortical Mitochondria:

The steroid productivity of compound of the present invention can beevaluated using rat adrenocortical mitochondria.

After intraperitoneal administration of 20 mg/mL cycloheximide solution(1 mL) to male SD rats, 101 U/mL adrenocorticotropic hormone (ACTH)solution (0.3 mL) is intraperitoneally administered to them in fiveminutes. 20 minutes after ACTH administration, the rats are sacrificedby cervical dislocation and bilateral adrenal cortexes are removed atonce. The removed adrenal cortexes are homogenized in buffer A(composition: 50 mmol/L Tris-HCl; 250 mmol/L sucrose) and then thesuspension is centrifuged at 2000 g for 3 minutes at 4 degreescentigrade. The obtained supernatant is centrifuged at 12500 g for 10minutes at 4 degrees centigrade. The pellet is washed with buffer Atwice and suspended in buffer B (composition: 250 mmol/L sucrose; 10mmol/L potassium phosphate buffer; 15 mmol/L triethanolamine; 20 mmol/Lpotassium chloride; 5 mmol/L magnesium chloride; 10 μmol/L trilostane;10 μmol/L SU10603) for experiments. Assay buffer which includes malicacid (150 mmol/L), β-NADP⁺ (5 mmol/L) and compound of the presentinvention is incubated for 5 minutes at 37 degrees centigrade. Then,crude mitochondrial membrane fraction derived from rat adrenal cortex isadded and further incubated for 10 minutes at 37 degrees centigrade toproduce pregnenolone (final concentration of the compound: 1 μmol/L).After incubation, the reaction is terminated by addition of ethanol,extracted by addition of n-hexane and then evaporated to dryness. Theresidue is dissolved in buffer C (composition: 0.1% gelatin; phosphatebuffered salts solution), centrifuged and then the collected supernatantis determined as samples for measurement. [³H] pregnenolone (10000 cpm;100 μL), anti-pregnenolone antibody (ICN Biomedicals Inc; 100 μL) andsample (100 μL) are mixed and incubated overnight at 4 degreescentigrade. After the reaction, the mixture is added by dextran/charcoal(200 μL), mixed well, kept on ice for 10 minutes and then centrifuged.The radioactivity of the supernatant is measured by liquid scintillationcounter. The pregnenolone in the sample is calculated from the standardcurve.

Effect of Compound of the Present Invention on Increase in PregnenolonContent in the Brain by Loading Stressor:

It can be confirmed that MBR antagonist can inhibit steroid productionin the brain, as follows.

Male Wistar rats are loaded with psychological stressor (Brain Res.,641, 21-28, 1994). Water is stored up to about 10 cm depth in acontainer of which the platform is set up at the center. Rats in thenon-treated group are loaded without administration and stressor. Incontrast, rats in the stressor loaded group are orally administered withthe vehicle or the compounds and 30 minutes later the rats are put onthe platform to be loaded with stressor. One hour later from starting toload, the rats are irradiated by microwave (output: about: about 6.5 kW,exposure time: 0.96 s) using microwave applicator (Muromachi Kikai Co.,Ltd.) and then the bilateral hippocampuses are removed and weighed. Thehippocampuses are added by internal standard substance (D₄-pregnenolone20 ng), water (1 mL) and diethylether/n-hexane (9:1, 3 mL) and stirred.The mixture is crushed by ultrasonic waves, stirred again, centrifugedat 3000 rpm for minutes and the organic layer is transferred to new tubewith Pasteur pipet. The water phase is extracted withdiethylether/n-hexane (9:1, 3 mL) again and the organic layer is mixedto the above described extract. After reduced pressure to dryness, theresidue is dissolved with 150 μL water/acetonitrile (1:9) again andmeasured by liquid chromatography/mass spectrometry (LC-MS). Themeasurement condition is shown as follows.

LC (Liquid chromatography): Hewlett Packard series 1100,

Column: Inertsil ODS-3, 3 μm, 2, 1^(ψ)×100 mm,

Temperature: room temperature,

Mobile phase: 5 mmol/L CH₃CO₂NH₄/MeCN (10:90),

Flow rate: 0.2 mL/min,

Injection volume: 40 μL,

MS (Micro spectrometry): Quattoro II (Micromass),

Ionization mode: Atmosphere Pressure Chemical Ionization (APCI),

positive; Corona: 3.4 kV,

Sheath gas: N2 (50 L/hr),

Source temperature: 180 degrees centigrade,

Probe temperature: 550 degrees centigrade,

Detection: Pregnenolone: m/z 317.2 (cone: 10V),

D₄-pregnenolone: m/z 321.2 (cone: 10V).

[Processes for the Preparation of Compound of the Present Invention]

The compound of the present invention represented by formula (I) can beprepared by combining the known processes, for example, the followingprocesses or the processes shown in Examples, which is the properlyimproved processes described in “Comprehensive Organic Transformations:A Guide to Functional Group Preparations, 2nd Edition”, “Richard C.Larock, John Wiley & Sons Inc, 1999”. Still, ingredients may be used assalts in the following each processes for the preparation. As thesesalts, the salts described as the pharmaceutically acceptable ones inthe above described formula (I) can be used.

a) Among the compounds represented by formula (I), the compound whereinX is a bond, Y is —C(═O)—, —C(═O)NR⁸—, —SO²—, —C(═O)O—, —SO²NR⁸—, thatis, the compound represented by formula (IA)

(wherein, Y¹ is —C(═O)—, —C(═O)NR⁸—, —SO₂—, —C(═O)O— or SO₂NR⁸—, theother symbols have the same meanings as the described above) can beprepared by following processes.

The compound represented by formula (IA) can be prepared by the compoundrepresented by formula (II)

(wherein, ring A¹⁻¹, ring A²⁻¹, R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹, R⁵⁻¹, R⁶⁻¹ orR⁷⁻¹ has the same meanings as that of ring A¹, ring A², R¹, R², R³, R⁴,R⁵, R⁶ or R⁷ respectively. But carboxyl, hydroxyl, amino or mercaptincluded the group represented by ring A¹⁻¹, ring A²⁻¹, R¹⁻¹, R²⁻¹,R³⁻¹, R⁴⁻¹, R⁵⁻¹, R⁶⁻¹ or R⁷⁻¹ is protected, if necessary), with thecompound represented by formula (III)L-Y¹⁻Z—B¹  (III)(wherein, L is a leaving group (e.g. halogen atom, imidazolyl etc.), B¹has the same meanings as that of B. But carboxyl, hydroxyl, amino ormercapt included the group represented by B¹ is protected, if necessary.The other symbols have the same meanings as the described above), ifnecessary, followed by subjecting to a deprotection reaction ofprotection group.

The reaction with the compound represented by formula (II) and thecompound represented by formula (III) is carried out, for example, byreacting the compound represented by formula (II) with the compoundrepresented by formula (III) in an organic solvent (e.g. chloroform,dichloromethane, diethylether, tetrahydrofuran etc.) under the presenceof a base (e.g. pyridine, triethylamine, dimethylaniline,dimethylaminopyridine, diisopropylethylamine etc.) at a temperature from−20 degrees centigrade to reflux temperature.

Or, it is carried out by reacting the compound represented by formula(II) with the compound represented by formula (III) in an organicsolvent (e.g. dioxane, tetrahydrofuran, diethylether etc.) usingalkaline solution (e.g. sodium bicarbonate or sodium hydroxide solutionetc.) at the temperature from 0 degrees centigrade to refluxtemperature.

The deprotectin reaction of a protective group for carboxyl, hydroxyl,amino, or mercapto is known, and it includes

(1) alkaline hydrosis,

(2) deprotection reaction under acidic conditions,

(3) deprotection reaction by hydrogenolysis,

(4) deprotection reaction of a silyl group,

(5) deprotection reaction using metals,

(6) deprotection reaction using metal complexes, and the like.

These methods are described concretely as follows.

(1) The deprotection reaction by alkaline hydrolysis is, for example,carried out in an organic solvent (e.g., methanol, tetrahydrofuran, ordioxane etc.) using a hydroxide of an alkali metal (e.g., sodiumhydroxide, potassium hydroxide, or lithium hydroxide etc.), a hydroxidealkaline earth metal (e.g., barium hydroxide, or calcium hydroxideetc.), or a carbonate (e.g., sodium carbonate or potassium carbonate,etc.), or an aqueous solution thereof, or a mixture thereof at atemperature of 0 to 40° C.

(2) The deprotection reaction under acidic conditions is carried out,for example, in an organic solvent (e.g., dichloromethane, chloroform,dioxane, ethyl acetate, or anisole etc.) in an organic acid (e.g.,acetic acid, trifluoroacetic acid, methansulfonic acid, or p-tosylate,etc.), or an inorganic acid (e.g., hydrochloric acid, or sulfuric acid,etc.) or a mixture thereof (e.g., hydrogen bormide/acetic acid, etc.) ata temperature of 0 to 100° C.

(3) The deprotection reaction by hydrogenolysis is carried out, forexample, in a solvent (e.g., ethers (e.g., tetrahydrofuran, dioxane,dimethoxyethane (DME), or diethylether, etc.), alcohols (e.g., methanol,or ethanol, etc.), benzenes (e.g., benzene, or toluene etc.), ketones(e.g., acetone, or methylethylketone, etc.), nitriles (e.g.,actetonitrile etc), amides (e.g., DMF etc.), water, ethyl acetate,acetic acid, or a mixed solvent of at least two of these etc.) in thepresence of a catalyst (e.g., palladium-carbon, palladium black,palladium hydroxide-carbon, platinum oxide, or Raney nickel, etc.) underthe hydrogen atomosphere at nomal pressure or under pressurization, orin the presence of ammonium formate at a temperature of 0 to 200° C.

(4) The deprotection reaction of a silyl group is carried out, forexample, in a water-miscible organic solvent (e.g., tetrahydrofuran, oracetonitrile, etc.) using tetrabutylammonium fluoride at a temperatureof 0 to 40° C.

(5) The deprotection reaction using metals is carried out, for example,in an acidic solvent (e.g., acetic acid, pH4.2-7.2 buffer solution, or amixture of a solution thereof and an organic solvent of tetrahydrofranetc.) in the presence of zinc powder, if necessary sonicating, at thetemperature of 0 to 40° C.

(6) The deprotection reaction using metal complexes is carried out, forexample, in an organic solvent (e.g., dichloromethane, DMF, THF, ethylacetate, acetonitrile, dioxane, ethanol etc.), water, or a mixturethereof, in the presence of a trap reagent (e.g., tributyltine hydride,triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.),an organic acid (e.g., acetic acid, formic acid, 2-ethyl hexanoic acid,etc.) and/or salts of organic acid (e.g., sodium 2-ethylhexanoate,potassium 2-ethylhexanoate etc.), in the presence or absence of aphosphine reagent (e.g., triphenylphosphine etc.), using metal complexes(e.g., tetrakistriphenylphosphinepalladium(0),dichlorobis(triphenylphosphine)palladium(II), palladium acetate(II),tris(triphenylphosphine)rhodium(I) chloride etc.) at the temperature of0 to 40° C.

In addition, the deprotection reaction except the above describedprocesses can be carried out, for example, by the process described inT. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York,1999.

The protection group for carboxyl includes, for example, methyl, ethyl,allyl, t-butyl, trichloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl,trityl, 2-chlorotrityl or structure thereof binded to solid phasecarrier and so on.

The protection group for hydroxyl includes, for example, methyl, trytyl,methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM),2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES),t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), acetyl (Ac),pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl(Alloc), 2,2,2-trichloroethoxycarbonyl (Trot), and so on.

The protection group of amino includes benzyloxycarbonyl,t-butoxycarbonyl, allyloxycarbonyl (Alloc),1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl,9-fluorenylinethoxycarbonyl, benzyl (Bn), p-methoxybenzyl,benzyloxymethyl (BOM), 2-(trimethylsilyl)ethoxymethyl (SEM) and so on.

The protection group of mercapto includes, for example, benzyl,methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP),diphenylmethyl, acetyl (Ac) and so on.

The protective group for carboxyl, hydroxyl, amino or mercapto is notparticularly limited to the above described groups, so long as it can beeasily and selectively left. For example, those described in T. W.Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999can be used.

As will be easily understood by those skilled in the art, the intendedcompounds in the present invention can be easily prepared by choosingthese deprotection reactions.

b) Among the compound represented by formula (I), the compounud whereinX is a bond, Y is —C(═O)NR⁸—, —C(═S)NR⁸—, that is, the compoundrepresented by formula (IB):

(wherein, Y² is —C(═O)NR⁸— or —C(═S)NR⁸—, the other symbols have thesame meanings as the described above) can be prepared by followingprocesses.

The compound represented by formula (IB) can be prepared by reacting thecompound represented by formula (IV):

(wherein, W is an oxygen atom or a sulfur atom, the other symbols havethe same meanings as the described above) with the compound representedby formula (V):

(wherein, all the symbols have the same meanings as the describedabove), if necessary, followed by subjecting to a deprotection reactionof protection group.

The reaction with the compound represented by formula (IV) and thecompound represented by formula (V) is carried out, for example, byreacting the compound represented by formula (IV) with the compoundrepresented by formula (V) in an organic solvent (e.g. chloroform,dichloromethane, diethylether, tetrahydrofuran etc.) under the presenceof a base (e.g. pyridine, triethylamine, dimethylaniline,dimethylaminopyridine, diisopropylethylamine etc.) at a temperature from0 degrees centigrade to reflux temperature.

Or, it is carried out by reacting the compound represented by formula(IV) with the compound represented by formula (V) in an organic solvent(e.g. dioxane, tetrahydrofuran, diethyl ether etc.) using alkali aqueoussolution (e.g. sodium bicarbonate or sodium hydroxide solution etc.) atthe temperature from 0 degrees centigrade to reflux temperature.

The deprotection reaction of the protective group can be carried out bythe above described method.

The compound represented by formula (IB) can be prepared by reacting thecompound represented by formula (II), the compound represented byformula (V) and the compound represented by formula (VI):

(wherein, all the symbols have the same meanings as the describedabove), if necessary, followed by subjecting to a deprotection reactionof protection group.

The reaction with the compound represented by formula (II), the compoundrepresented by formula (V) and the compound represented by formula (VI)is carried out, for example, by reacting the compound represented byformula (II), the compound represented by formula (V), the compoundrepresented by formula (VI) (for example, phosgene compound (e.g.phosgene, thiophosgene, triphosgene(bis(trichloromethyl)carbonate)etc.), imidazole compound (e.g. CDI (carbonyldiimidazole), TCDI(thiocarbonylimidazole) etc.) in an organic solvent (e.g. ethyl acetate,chloroform, dichloromethane, diethylether, tetrahydrofuran, benzene,toluene etc.) or absence of solvent and under the presence of a base(e.g. pyridine, triethylamine, dimethylaniline, dimethylaminopyridine,diisopropylethylamine etc.) at a temperature from −20 degrees centigradeto reflux temperature.

This reaction is preferably carried out under the anhydrous condition inthe presence of inert gases.

The deprotection reaction of the protective group can be carried out bythe above described method.

c) Among the compound represented by forumula (I), the compound whereinX is a bond, Y is —C(═O)NH—, —C(═S)NH—, that is, the compoundrepresented by formula (IC):

(wherein, all the symbols have the same meanings as the described above)can be prepared by reacting the compound represented by formula (II) andthe compound represented by formula (VII)W═C═N—Z—B¹  (VII)(wherein, all the symbols have the same meanings as the describedabove), if necessary, followed by subjecting to a deprotection reactionof protection group.

The reaction with the compound represented by formula (II) and thecompound represented by formula (VII) is carried out, for example, byreacting the compound represented by formula (II) with the compoundrepresented by formula (VII) in an organic solvent (e.g. toluene,benzene, xylene, tetrahydrofuran, dichloromethane, diethylether,1,2-dichloroethane, N,N-dimethylformamide etc.) at a temperature from 0degrees centigrade to reflux temperature.

This reaction is preferably carried out under the anhydrous condition inthe presence of inert gases.

The deprotection reaction of the protective group can be carried out bythe above described method.

d) Among the compounds represented by formula (I), the compound whereinA is a heterocyclic ring containing at least one nitrogen atom, X isC1-3 alkylene which may have a substituent(s), C2-3 alkenylene which mayhave a substituent(s), C2-3 alkynylene which may have a substituent(s),Y is —C(═O)NR⁸—, —SO₂—, —C(═O)O—, —SO₂NR⁸—, that is, the compoundrepresented by formula (ID):

(wherein, X² is C1-3 alkylene which may have a substituent(s), C2-3alkenylene which may have a substituent(s) or C2-3 alkynylene which mayhave a substituent(s), the other symbols have the same meanings as thedescribed above) can be prepared by the following process.

The compound represented by formula (ID) can be prepared by reacting thecompound represented by formula (II) and the compound represented byformula (VIII):L¹-X²—Y¹—Z—B¹  (VIII)(wherein, L¹ is a halogen atom, the other symbols have the same meaningsas the described above), if necessary, followed by subjecting to adeprotection reaction of protection group.

The reaction with the compound represented by formula (II) and thecompound represented by formula (VIII) is carried out, for example, inan organic solvent (e.g. tetrahydrofuran, dichloromethane, chloroform,benzene, toluene, xylene, hexane, heptane, cyclohexane, diethylether,dioxane, acetone, ethylmethylketone, acetonitrile, dimethylsulfoxide,N,N-dimethylformamide, dimethylacetamide, ethyl acetate etc.), under thepresence of a base (e.g. potassium carbonate, sodium carbonate, cesiumcarbonate, sodium hydride etc.), and under the presence or the absenceof a catalyst (e.g. potassium iodide, sodium iodide, tetrabutyl ammoniumiodide etc) at a temperature from 0 degrees centigrade to refluxtemperature.

The deprotection reaction of the protective group can be carried out bythe above described method.

e) Among the compound represented by formula (I), the compound wherein Xis a bond, Y is —C(═O)—, or —C(═S)—, that is, the compound representedby formula (IE):

(wherein, all the symbols have the same meanings as the described above)can be prepared by the following process.

The compound represented by formula (IE) can be prepared by the compoundrepresented by formula (II) and the compound represented by formula(IX):

(wherein, all the symbols have the same meanings as the describedabove), if necessary, followed by subjecting to a deprotection reactionof protection group.

The reaction with the compound represented by formula (II) and thecompound represented by formula (XI) is carried out, for example, by themethod (1) using acid halide, (2) using mixed acid anhydride, (3) usingcondensing agent etc.

These methods are explained concretely as follows.

(1) The method using acid halide is carried out, for example by reactingthe compound represented by formula (XI) in an organic solvent (e.g.chloroform, dichloroform, diethylether, tetrahydrofuran, dimethoxyethaneetc.) or the absence of solvent, with acid halide agent (e.g.oxalylchloride, thionylchloride etc.) at the temperature from −20degrees centigrade to reflux temperature, and reacting the obtained acidhalide with the compound represented by formula (II) in a organicsolvent (e.g. chloroform, dichloromethane, diethylether,tetrahydrofuran, acetonitrile, ethyl acetate etc.) under the presence ofa base (e.g. pyridine, triethylamine, dimethylaniline,dimethylaminopyridine, diisopropylethylamine etc.) at the temperature offrom 0 to 40 degrees centigrade. In addition, it is carried out byreacting the obtained halide with the compound represented by formula(II) in an organic solvent (e.g. dioxane, tetrahydrofuran,dichloromethane etc.), under the presence or absence of phase-transfercatalyst (e.g. quaternary ammonium salt etc., for example,tetrabutylammoniumchloride, triethylbenzylammoniumchloride, trin-octylmethylammoniumchloride, trimethyldecylammoniumchloride,tetramethylammoniumbromide and so on), using alkaline solution (e.g.sodium bicarbonate or sodium hydroxide solution etc.) at the temperaturefrom 0 to 40 degrees centigrade.

(2) The method using mixed acid anhydride is carried out, for examplethe compound represented by formula (XI) with an acid halide (e.g.pivaloyl chloride, tosyl chloride, mesyl chloride etc.), or an acidderivative (e.g. chloroethyl formate, chloroisobutyl formate etc.) in anorganic solvent (e.g. chloroform, dichloromethane, diethylether,tetrahydrofuran etc.) or the absence of solvent, under the presence of abase (e.g. pyridine, triethylamine, dimethylaniline,dimethylaminopyridine, diisopropylethylamine etc.) at the temperaturefrom 0 to 40 degrees centigrade, and by reacting the obtained mixed acidanhydride with the compound represented by formula (II) in an organicsolvent (e.g. chlorofolin, dichloromethane, diethylether,tetrahydrofuran etc.) at the temperature from 0 to 40 degreescentigrade.

(3) The method using condensing agent is carried out, for example byreacting the compound represented by formula (XI) with the compoundrepresented by formula (II) in an organic solvent (e.g. chloroform,dichloromethane, dimethylformamide, diethylether, tetrahydrofuran etc.),or in the absence of solvent, under the presence or the absence of abase (e.g. pyridine, triethylamine, dimethylaniline,dimethylaminopyridine etc.) using the condensing agent (e.g.1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine,1-propanephosphonic acid cyclic anhydride (PPA) etc.), using or notusing 1-hydroxybenztriazole (HOBt) at the temperature from 0 to 40degrees centigrade.

These reactions (1), (2) and (3) are all preferably carried out underthe anhydrous condition in the presence of inert gases (argon, nitrogenetc.).

The deprotection reaction of the protective group can be carried out bythe above described method.

The compounds represented by formula (II), (III), (IV), (V), (VI),(VII), (VIII) and (IX) used as starting materials or reagents can beeasily prepared by the known processes, the processes shown in followingExamples, or the known processes, for example, processes described in“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2nd Edition”, “Richard C. Larock, John Wiley & Sons Inc,1999”.

In each reaction in the present specification, as will be understood bythose skilled in the art, the reaction with heating can be effectedusing water bath, oil bath, sand bath or microwave.

In each reaction in the present specification, solid-phase supportedreagent accordingly supported to macromolecule polymer (e.g.polystyrene, polyacrylamide, polypropylene, polyethyleneglycol etc.) maybe used.

In each reaction in the present specification, reaction products may bepurified in an ordinary manner, for example, through normal-pressure orreduced-pressure distillation, or through high-performance liquidchromatography with silica gel or magnesium silicate, thin-layerchromatography, or column chromatography, ion-exchange resin, scavengerresin or through washing or recrystallizaion and so on. The purificationmay be effected in each reaction or after some reactions

[Toxicity]

Toxicity of the compound represented by formula (I) is very low, and itis safe enough to use as a pharmaceutical agent.

[Application to Pharmaceutical Preparations]

The compound represented by formula (I), a salt thereof, an N-oxidethereof, a solvate thereof or a prodrug thereof (hereinafter, it isabbreviated to the compound of the present invention) is useful for apreventive and/or therapeutic agent for the above described diseasescaused by stress in mammals (e.g. human, non-human animal (e.g. monkey,sheep, cow, horse, dog, cat, rabbit, rat, mouse etc.) etc.). Thecompound of the present invention is useful for a preventive and/ortherapeutic agent for, particularly, digestive system disease caused bystress (irritable bowel syndrome, ulcerative colitis, Crohn's diseaseetc.).

The compounds of the present invention may be administered incombination with other pharmaceutical preparations for the purpose of 1)complement and/or enhancement of preventing and/or treating effect ofthe compounds of the present invention, 2) improvement ofdynamics/absorption and lowering of dose of the compounds of the presentinvention and/or 3) alleviation of side effect of the compounds of thepresent invention.

The compounds of the present invention and other pharmaceuticalpreparations may be administered in the form of formulation having thesecomponents incorporated in one preparation or may be administered inseparate preparations. In the case where these pharmaceuticalpreparations are administered in separate preparations, they may beadministered simultaneously or at different times. In the latter case,the compounds of the present invention may be administered before theother pharmaceutical preparations. Alternatively, the otherpharmaceutical preparations may be administered before the compounds ofthe present invention. The method for the administration of thesepharmaceutical preparations may be same or different.

The other pharmaceutical preparations may be low-molecular compounds. Inaddition, they may be macromolecular protein, polypeptide,polynucleotide (DNA, RNA, and gene), antisense, decoy, antibody orvaccine and so on. The dose of the other pharmaceutical preparations canbe accordingly selected as a standard of clinical dose. Additionally,the compounding ratio of the compounds of the present invention and theother pharmaceutical preparations can be accordingly selected by the ageand body weight of administering object, the administration method, theadministration time, the object disease, the symptom, the combinationetc. For example, the other pharmaceutical preparations may be used from0.01 to 100 parts by weight relative to 1 part by weight of thecompounds of the present invention. The other pharmaceuticalpreparations may be administered at appropriate ratio combining one ormore arbitrarily selected from the homogeneous groups or heterogeneousgroups as follows. The other pharmaceutical preparations do not onlyinclude ones which have ever been found but ones which will be foundfrom now based on the above described mechanism.

The other pharmaceutical preparations which may combine the compounds ofthe present invention include, for example, antianxiety drugs (e.g.benzodiazepine drugs, thienodiazepine drugs, non-benzodiazepine drugs,serotonergic drugs, CRF antagonists, tachykinin NK₁ antagonists etc.),antidepressants (e.g. tricyclic antidepressants, tetracyclicantidepressants, monoamine release drugs, monoamine oxidase inhibitors,monoamine reuptake inhibitors (SSRI, SNRI), CRF antagonists, tachykininNK₁ antagonists, neurotensin antagonists etc.), antiparkinson drugs(e.g. anticholinergic drugs, dopamine agonists, monoamine oxidaseinhibitors, etc.), schizophrenia drugs (e.g. dopamine antagonists,etc.), antiepileptic drugs (e.g. barbituric acid series, hydantoinseries etc.), anti vertigo drugs, asthmatic drugs (e.g. bronchodilators,a receptor agonists, β₂ receptor agonists, xanthine series, inhaledsteroids, anticholinergic drugs, 5-lipoxygenase inhibitors etc.), pepticulcer drugs (e.g. offensive factor inhibitors, antipeptic drugs,antacids, histamine-H₂ receptor antagonists, anti gastrin drugs, protonpump inhibitors, muscarine receptor inhibitors, anticholinergic drugs,defensive factor enhancers, prostaglandin derivatives, etc.),gastrointestinal tract function regulators (e.g. intestinal remedies,CCK-A antagonists, neurotensin antagonists, opioid agonists, muscarinereceptor agonists, 5-HT₄ agonists, 5-HT₃ antagonists etc.),gastrointestinal tract prokinetic drugs (e.g. intestinal remedies, CCK-Aantagonists, neurotensin antagonists, opioid agonists, muscarinereceptor agonists, 5-HT₄ agonists, 5-HT₃ antagonists etc.),antidiarrheals (e.g. antidiarrheal drugs, opioid μ receptor stimulators,etc.), evacuants (e.g. bulk laxatives, saline laxatives, stimulantlaxatives, affinity polyacrylic resin etc.), antihypertensive drugs(e.g. calcium antagonists, β receptor blockers, α₁ receptor blockers,angiotensin converting enzyme inhibitors, angiotensin II receptorblockers, etc.), antiarrhythmic drugs (e.g. sodium inhibitors, βreceptor blockers, potassium antagonists, calcium antagonists, etc.),cardiac stimulants (e.g. phosphodiesterase inhibitors, cardiacglycosides, β receptor agonists etc.), dysuria remedies (e.g. frequenturination remedies, anticholinergic drugs, muscarine agonists(antagonists), tachykinin NK₁ antagonists, NK₂ antagonists, etc.) and soon.

The diseases on which the preventive and/or therapeutic effect workswith the above described combination drugs are not especially limited.The diseases may be those which compensate for and/or enhance thepreventive and/or therapeutic effect of the compounds of the presentinvention.

The other pharmaceutical preparations to compensate and/or enhance forpreventive and/or therapeutic effect on irritable bowel syndrome of thecompounds of the present invention include, for example, antianxietydrugs (e.g. benzodiazepine drugs, thienodiazepine drugs,non-benzodiazepine drugs, serotonergic drugs, CRF antagonists etc.),antidepressants (e.g. monoamine release drugs, monoamine oxidaseinhibitors, monoamine reuptake inhibitors (SSRI, SNRI), CRF antagonists,neurotensin antagonists, tricyclic antidepressants, tetracyclicantidepressants, etc.), anticholinergic drugs, gastrointestinal tractfunction regulators (e.g. intestinal remedies, CCK-A antagonists,neurotensin antagonists, opioid agonists, muscarine receptor agonists,5-HT₄ agonists, 5-HT₃ antagonists etc.), gastrointestinal tractprokinetic drugs (e.g. intestinal remedies, CCK-A antagonists,neurotensin antagonists, opioid agonists, muscarine receptor agonists,5-HT₄ agonists, 5-HT₃ antagonists etc.), antidiarrheals (e.g.antidiarrheal drugs, opioid μ receptor stimulators, etc.), evacuants(e.g. bulk laxatives, saline laxatives, stimulant laxatives, affinitypolyacrylic resin etc.), mucosal paralytic drugs, autonomic nervemodulators, calcium antagonists, phosphodiesterase inhibitors, serotoninantagonists (e.g. 5-HT₃ antagonists, 5-HT₄ antagonists etc.),darifenacyn, polycarbophil calcium and so on.

The other pharmaceutical preparations to compensate and/or enhance forpreventive and/or therapeutic effect on gastric ulcer and duodenal ulcerof the compounds of the present invention include, for example, pepticulcer drugs (e.g. offensive factor inhibitors, antipeptic drugs,antacids, histamine-H₂ receptor antagonists, anti gastrin drugs, protonpump inhibitors, muscarine receptor inhibitors, anticholinergic drugs,defensive factor enhancers, prostaglandin derivatives, mesalazine,salazosulfapyridine, etc.), anticholinergic drugs, gastric mucosalparalytic drugs, antianxiety drugs (e.g. benzodiazepine drugs,thienodiazepine drugs, non-benzodiazepine drugs, serotonergic drugs, CRFantagonists, etc.), dopamine antagonists and so on.

The other pharmaceutical preparations to compensate and/or enhance forpreventive and/or therapeutic effect on ulcerative colitis of thecompounds of the present invention include, for example, mesalazine,salazosulfapyridine, peptic ulcer drugs (e.g. offensive factorinhibitors, antipeptic drugs, antacids, histamine-H₂ receptorantagonists, anti gastrin drugs, proton pump inhibitors, muscarinereceptor inhibitors, anticholinergic drugs, defensive factor enhancers,prostaglandin derivatives, etc.), anticholinergic drugs, steroids,5-lipoxygenase inhibitors, antioxidant drugs, LTB₄ antagonists, localanesthetics, immunosuppressive drugs, defensive factor enhancers,metalloprotease inhibitors and so on.

The other pharmaceutical preparations to compensate and/or enhance forpreventive and/or therapeutic effect on biliary tract dyskinesia of thecompounds of the present invention include, for example, ceruleins,antispasmodic drugs, COMT (catechol-O-methyltransferase) inhibitors,cholinergic agonists, anticholinergic drugs, antianxiety drugs,cholagogues, antidepressants, CCK-A antagonists and so on.

The other pharmaceutical preparations to compensate and/or enhance forpreventive and/or therapeutic effect on aerophagy of the compounds ofthe present invention include, for example, intestinal remedies,antianxiety drugs, autonomic nerve modulators, fiber formulations,digestive enzymes, gas absorbent drugs, intestinal tract prokineticdrugs and so on.

The other pharmaceutical preparations to compensate and/or enhance forpreventive and/or therapeutic effect on chronic hepatitis of thecompounds of the present invention include, for example, liverhydrolysate formulations, polyenephosphatidylcholine, glycyrrhizinformulations, protoporphyrin sodium, ursodeoxycholic acid, steroids,anticholinergic drugs, antacids, propagermanium, lipid peroxidaseinhibitors and so on.

The other pharmaceutical preparations to compensate and/or enhance forpreventive and/or therapeutic effect on chronic pancreatitis of thecompounds of the present invention include, for example, proteaseinhibitors, gastric acid inhibitors, antispasmodic drugs (e.g. COMTinhibitors, anti serotonin drugs etc.), nonsteroidal anti-inflammatorydrugs, central analgesics, sedatives, digestive enzymes, antacids,histamine H₂ receptor inhibitors, antidepressants, gastric mucosa localanesthetics, gastrointestinal tract function regulators (CCK-Aantagonists) and so on.

The other pharmaceutical preparations to compensate and/or enhance forpreventive and/or therapeutic effect on esophageal spasm of thecompounds of the present invention include, for example, esophagealprokinetic drugs, antidepressants, autonomic nerve modulators and so on.

The other pharmaceutical preparations to compensate and/or enhance forpreventive and/or therapeutic effect on gastric atony of the compoundsof the present invention include, for example, gastrointestinal tractprokinetic drugs, digestive enzymes, tranquilizers and so on.

The other pharmaceutical preparations to compensate and/or enhance forpreventive and/or therapeutic effect on functional dyspepsia of thecompounds of the present invention include, for example, antacids,histamine H₂ receptor inhibitors, gastrointestinal tract functionregulators, gastrointestinal tract prokinetic drugs, antidepressants,tranquilizers, digestive enzymes, proton pump inhibitors, muscarinereceptor inhibitors, anticholinergic drugs, defensive factor enhancers,dopamine antagonists and so on.

Antianxiety drugs include, for example, diazepam, oxazolam,flunitrazepam, alprazolam, etizolam, flutazolam, lorazepam, ethylloflazepate, tofisopam, clotiazepam, yoryzanol and so on.

Tricyclic antidepressants include, for example, amitriptyline,imipramine, clomipramine, nortriptyline, desipramine, amoxapine and soon.

Tetracyclic antidepressants include, for example, mianserin, maprotilineand so on.

Monoamine oxidase inhibitors include, for example, trazodone,fluvoxamine and so on.

Antiparkinson drugs include, for example, levodopa, amantadine,selegiline, bromocriptine, pramipexole, anticholinergic drug and so on.

Anticholinergic drugs include, for example, trihexyphenidyl, biperiden,ipratropium bromide, mepenzolate bromide and so on.

Antiepileptic drugs include, for example, phenobarbital, phenyloin,carbamazepine, valproic acid, clonazepam and so on.

Anti vertigo drugs include, for example, difenidol, Phistine and so on.

Asthmatic drugs include, for example, ephedrine, orciprenaline,salbutamol, procaterol, theophylline, aminophylline, disodiumcromoglycate, anticholinergic drug, inhaled steroid and so on.

Inhaled steroids include, for example, beclomethasone, prednisolone andso on.

Antipeptic drugs include, for example, sucralfate and so on.

Antacids include, for example, sodium bicarbonate, magnesium oxide, dryaluminum hydroxide gel, aluminum silicate and so on.

Histamine H₂ receptor antagonists include, for example, famotidine,ranitidine, cimetidine, roxatidine and so on.

Anti gastrin drugs include, for example, proglumide and so on.

Proton pump inhibitors include, for example, omeprazole, lansoprazoleand so on.

Muscarine receptor inhibitors include, for example, pirenzepine and soon.

Defensive factor enhancers include, for example, gefarnate, teprenone,sucralfate, aldioxa, cetraxate hydrochloride, ornoprostil and so on.

Prostaglandin derivatives include, for example, ornoprostil, misoprostoland so on.

Gastrointestinal tract function regulators include, for example,cisapride, domperidone, sulpiride, metoclopramide, alosetron,trimebutine maleate and so on.

Gastrointestinal tract prokinetic drugs include, for example, cisapride,tegaserod, bethanechol hydrochloride and so on.

Antidiarrheals include, for example, loperamide and so on.

Bulk laxatives include, for example, methylcellulose, carmellose,lactulose and so on.

Saline laxatives include, for example, magnesium sulfate, magnesiumoxide and so on.

Stimulant laxatives include, for example, picosulfate, lactulose, castoroil, senna, rhubarb and so on.

Antihypertensive drugs include, for example, nicardipine, nifedipine,nilvadipine, atenolol, allotynol, carteolol, propranolol, metoprolol,prazosin, captopril, enalapril, candesartan cilexetil, losartanpotassium and so on.

Antiarrhythmic drugs include, for example, quinidine, procainamide,disopyramide, lidocaine, mexiletine, propranolol, amiodarone, verapamiland so on.

Cardiac stimulants include, for example, digitoxin, digoxin, dopamine,dobutamine, aminophylline, mirnoline and so on.

Dysuria remedies include, for example, oxybutynin, tamsulosin,propiverine and so on.

Local anesthetics include, for example, lidocaine, oxethazaine, procainehydrochloride, dibucaine hydrochloride, cocaine hydrochloride,tetracaine hydrochloride and so on.

Immunosuppressive drugs include, for example, cyclosporine, tacrolimus,azathiopurine, FTY720 and so on.

Autonomice nerve modulators include, for example, yorizanol and so on.

Cholagogues include, for example, ursodeoxycholic acid and so on.

Tachykinin NK₁ antagonists include, for example, aprepitant, TAK-637,Z-501 and so on.

Serotonin antagonists include, for example, YM060, tegaserod, alosetronand so on.

In order to use the compounds of the present invention, or the compoundsof the present invention in combination with the other pharmaceuticalpreparations by the above described purpose, these compounds arenormally administered to the entire of human body or topically, andorally or parenterally.

The dose of the compounds of the present invention depends on age, bodyweight, symptom, therapeutic effect, the administration method, thetreatment time and so on. In practice, however, these compounds areadministered orally once or several times per day each in an amount offrom 100 μg to 1000 mg per adult, parentally once or several times perday each in an amount of from 50 μg to 500 mg per adult or continuouslyadministered into vein for 1 hour to 24 hours per day.

It goes without saying that the dose of these compounds may be less thanthe above described dose or may need to exceed the above described rangebecause the dose varies under various conditions as described above.

When the compounds of the present invention, or the compounds of thepresent invention are administered in combination with the otherpharmaceutical preparations, they are used in the form of solid orliquid agent for oral administration, injection, agent for externalapplication, suppository, eye drops or inhalant for parenteraladministration or the like.

Examples of the solid agent for oral administration include tablet,pill, capsule, powder, and pellet. Examples of the capsule include hardcapsule, and soft capsule.

In such a solid agent for internal application, one or more activematerials are used in the form of preparation produced by an ordinarymethod singly or in admixture with a vehicle (e.g., lactose, mannitol,glucose, microcrystalline cellulose, starch etc.), binder (e.g.,hydroxypropyl cellulose, polyvinyl pyrrolidone, magnesiummetasilicoaluminate etc.), disintegrant (e.g., calcium fibrinoglycolateetc.), glidant (e.g., magnesium stearate etc.), stabilizer, dissolutionaid (e.g., glutamic acid, aspartic acid etc.) or the like. The solidagent may be coated with a coating agent (e.g., white sugar, gelatin,hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate etc.)or two or more layers. Alternatively, the solid agent may be capsulizedby an absorbable material such as gelatin.

Examples of the liquid agent for oral administration includepharmaceutically acceptable aqueous solution, suspension, emulsion,syrup, and elixir. In such a liquid agent, one or more active agents aredissolved, suspended or emulsified in a commonly used diluent (e.g.,purified water, ethanol, mixture thereof etc.). Furthermore, such aliquid agent may comprise a wetting agent, a suspending agent, anemulsifier, a sweetening agent, a flavor, a fragrance, a preservative, abuffer, etc.

The agent for parenteral administration may be in the form of, e.g.,ointment, gel, cream, wet compress, paste, liniment, nebula, inhalant,spray, aerosol, eye drops, collunarium or the like. These agents eachcontain one or more active materials and are prepared by any knownmethod or commonly used formulation.

The ointment is prepared by any known or commonly used formulation. Forexample, one or more active materials are triturated or dissolved in abase to prepare such an ointment. The ointment base is selected fromknown or commonly used materials. In some detail, higher aliphatic acidor higher aliphatic acid ester (e.g., adipic acid, myristic acid,palmitic acid, stearic acid, oleic acid, adipic acid ester, myristicacid ester, palmitic acid ester, stearic acid ester, oleic acid esteretc.), wax (e.g., beeswax, whale wax, ceresin etc.), surface activeagent (e.g., polyoxyethylenealkylether phosphoric acid ester etc.),higher alcohol (e.g., cetanol, stearyl alcohol, setostearyl alcoholetc.), silicon oil (e.g., dimethyl polysiloxane etc.), hydrocarbon(e.g., hydrophilic petrolatum, white petrolatum, purified lanolin,liquid paraffin etc.), glycol (e.g., ethylene glycol, diethylene glycol,propylene glycol, polyethylene glycol, macrogol etc.), vegetable oil(e.g., castor oil, olive oil, sesame oil, turpentine oil), animal oil(mink oil, vitelline oil, squalane, squalene), water, absorptionaccelerator and rash preventive may be used singly or in admixture oftwo or more thereof. The base may further comprise a humectant, apreservative, a stabilizer, an antioxidant, a perfume, etc.

The gel is prepared by any known or commonly used formulation. Forexample, one or more active materials are dissolved in a base to preparesuch a gel. The gel base is selected from known or commonly usedmaterials. For example, lower alcohol (e.g., ethanol, isopropyl alcoholetc.), gelling agent (e.g., carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, ethyl cellulose etc.), neutralizingagent (e.g., triethanolamine, diisopropanolamine etc.), surface activeagent (e.g., polyethylene glycol monostearate etc.), gums, water,absorption accelerator, and rash preventive are used singly or inadmixture of two or more thereof. The gel base may further comprise apreservative, an antioxidant, a perfume, etc.

The cream is prepared by any known or commonly used formulation. Forexample, one or more active materials are dissolved in a base to preparesuch a cream. The cream base is selected from known or commonly usedmaterials. For example, higher aliphatic acid ester, lower alcohol,hydrocarbon, polyvalent alcohol (e.g., propylene glycol, 1,3-butyleneglycol etc.), higher alcohol (e.g., 2-hexyl decanol, cetanol etc.),emulsifier (e.g., polyoxyethylene alkyl ethers, aliphatic acid estersetc.), water, absorption accelerator, and rash preventive are usedsingly or in admixture of two or more thereof. The cream base mayfurther comprise a preservative, an antioxidant, a perfume, etc.

The wet compress is prepared by any known or commonly used formulation.For example, one or more active materials are dissolved in a base toprepare a kneaded mixture which is then spread over a support to preparesuch a wet compress. The wet compress base is selected from known orcommonly used materials. For example, thickening agent (e.g.,polyacrylic acid, polyvinyl pyrrolidone, gum arabic, starch, gelatin,methyl cellulose etc.), wetting agent (e.g., urea, glycerin, propyleneglycol etc.), filler (e.g., kaolin, zinc oxide, talc, calcium, magnesiumetc.), water, dissolution aid, tackifier, and rash preventive may beused singly or in admixture of two or more thereof. The wet compressbase may further comprise a preservative, an antioxidant, a perfume,etc.

The pasting agent is prepared by any known or commonly used formulation.For example, one or more active materials are dissolved in a base toprepare a kneaded mixture which is then spread over a support to preparesuch a pasting agent. The pasting agent base is selected from known orcommonly used materials. For example, polymer base, fat and oil, higheraliphatic acid, tackifier and rash preventive may be used singly or inadmixture of two or more thereof. The pasting agent base may furthercomprise a preservative, an antioxidant, a perfume, etc.

The liniment is prepared by any known or commonly used formulation. Forexample, one or more active materials are dissolved, suspended oremulsified in water, alcohol (e.g., ethanol, polyethylene glycol etc.),higher aliphatic acid, glycerin, soap, emulsifier, suspending agent,etc., singly or in combination of two or more thereof, to prepare such aliniment. The liniment may further comprise a preservative, anantioxidant, a perfume, etc.

The nebula, inhalant, spray and aerozol each may comprise a commonlyused diluent, additionally, a stabilizer such as sodium hydrogen sulfiteand a buffer capable of providing isotonicity such as isotonic agent(e.g., sodium chloride, sodium citrate, or citric acid etc.). For theprocess for the preparation of spray, reference can be made to U.S. Pat.Nos. 2,868,691 and 3,095,355.

The injection for parenteral administration consists of solid injectionused to be dissolved or suspended in the form of solution, suspension,emulsion and a solvent to be dissolved before use. The injection isprepared by dissolving, suspending or emulsifying one or more activematerials in a solvent. As such a solvent there may be used distilledwater for injection, physiological saline, vegetable oil, alcohol suchas propylene glycol, polyethylene glycol and ethanol, etc., singly or incombination thereof. The injection may further comprise a stabilizer, adissolution aid (e.g., glutamic acid, aspartic acid, Polysolvate 80(trade name) etc.), a suspending agent, an emulsifier, a soothing agent,a buffer, a preservative, etc. The injection is sterilized at the finalstep or prepared by an aseptic process. Alternatively, an aseptic solidagent such as freeze-dried product which has previously been preparedmay be rendered aseptic or dissolved in aseptic distilled water forinjection or other solvents before use.

The eye drops for parenteral administration consist of eye drop,suspension eye drop, emulsion eye drop, eye drop to be dissolved beforeuse and ointment and so on.

These eye drops are prepared by a known method. For example, it isprepared by dissolving, suspending or emulsifying one or more activematerials in a solvent. As such a solvent for eye drops there may beused distilled water, physiological saline, the other aqueous solvent ornonaqueous solvent for injection (e.g. vegetable oil etc.), etc., singlyor in combination thereof. The eye drops may comprise, if necessary, ofmaterials properly selected from tonisity agent (e.g. sodium chloride,concentrated glycerin etc.), buffer agents (e.g. sodium phosphate,sodium acetate etc.), surfactants (e.g. polysorbate 80 (trade name),polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil etc.),stabilizer (e.g. sodium citrate, sodium edentate etc.), antiseptic agent(e.g. benzalkonium chloride, paraben etc.) These are sterilized at thefinal step or prepared by an aseptic process. Alternatively, an asepticsolid agent such as freeze-dried product which has previously beenprepared may be rendered aseptic or dissolved in aseptic distilled waterfor injection or other solvents before use.

The inhalant for parenteral administration may be in the form ofaerosol, powder for inhalation or liquid for inhalation. The liquid forinhalation may be dissolved or suspended in water or other proper mediumin use.

These inhalants are prepared by a known method.

For example, the liquid for inhalation is prepared from materialsproperly selected from preservatives (e.g., benzalconiurn chloride,Paraben etc.), colorants, buffering agents (e.g., sodium phosphate,sodium acetate etc.), isotonic agents (e.g., sodium chloride,concentrated glycerin etc.), thickening agents (e.g., carboxyvinylpolymer etc.), absorption accelerators, etc. as necessary.

The powder for inhalation is prepared from materials properly selectedfrom glidants (e.g., stearic acid and salt thereof etc.), binders (e.g.,starch, dextrin etc.), vehicles (e.g., lactose, cellulose etc.),colorants, preservatives (e.g., benzalconium chloride, Paraben etc.),absorption accelerators, etc., if necessary.

In order to administer the liquid for inhalation, a sprayer (e.g.,atomizer, nebulizer etc.) is normally used. In order to administer thepowder for inhalation, a powder inhaler is normally used.

Other examples of the composition for parenteral administration includesuppository for rectal administration and pessary for vaginaladministration prepared by an ordinary formulation comprising one ormore active materials.

Effect of the Invention

The compound of the present invention represented by formula (I) has anaffinity to MBR and further anti stress action. Among the compound ofthe present invention represented by formula (I), since the compound ofwhich ring A² has two substituents, that is, the compound of the presentinvention represented by formula (I-B-1-2) has a strong affinity to MBR,shows strong anti stress action and superior to oral absorption, it isuseful as a preventive and/or therapeutic agent for diseases caused bystress, especially, digestive system diseases caused by stress.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph which shows a suppressive action for abdominal pain ofthe compound of the present invention in RCS loaded model.

BEST MODE OF THE CARRYING OUT THE INVENTION

The present invention is explained below in detail base on Examples,however, the present invention is not limited thereto. The solvents inparentheses at chromatographic separations section and TLC section showthe developing or eluting solvents and the ratios of the solvents usedare indicated by volume. The solvents in parentheses indicated in NMRsection show solvents used in determination.

All compounds described in the specification are named by using ofACD/Name (Trade mark, Advanced Chemistry Development Inc.) or ACD/Namebatch (Trade mark, Advanced Chemistry Development Inc.) which is thecomputer program to name according to IUPAC rule, or according to IUPACorganic chemistry nomenclature.

Example 1 1-(1H-indole-3-yl)cyclopropanecarbonitrile

1H-indole-3-ylacetonitrile (18.7 g) was dissolved in tetrahydrofuran(240 mL) and, after cooling to −30° C., lithium diisopropylamide (2.0Mheptane/tetrahydrofuran/ethylbenzene solution, 240 mL) was addeddropwise, followed by stirring at −5° C. for 30 minutes. The reactionmixture was cooled to −30° C. and 1-bromo-2-chloroethane (11.0 mL) wasadded dropwise, followed by stirring for 2 hours while heating to 0° C.The reaction mixture was poured into ice/hydrochloric acid (2N, 360 mL)and extracted with ethyl acetate. The organic layer was washed in turnwith water, an aqueous saturated sodium hydrogen carbonate solution andsaturated saline, dried over anhydrous magnesium sulfate and thenconcentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=3:1) to obtain a compound and thecompound was recrystallized from (hexane:ethyl acetate=1:1) to obtainthe titled compound having the following physical properties (8.67 g).

TLC: Rf 0.43 (hexane:ethyl acetate=2:1);

¹H NMR (CDCl₃): δ 1.30-1.43 (m, 2H), 1.60-1.75 (m, 2H), 7.11 (d, J=2.74Hz, 1H), 7.16-7.32 (m, 2H), 7.33-7.45 (m, 1H), 7.72-7.90 (m, 1H), 8.11(s, 1H).

Example 2 [1-(1H-indole-3-yl)cyclopropyl]methylamine

To an anhydrous tetrahydrofuran (35 mL) suspension of lithium aluminumhydride (1.07 g), an anhydrous tetrahydrofuran (12 mL) solution of acompound (1.71 g) prepared by Example 1 was added dropwise at 80° C.,followed by stirring at 80° C. until materials disappear. The reactionmixture was air-cooled to room temperature and water (1 mL), an aqueous5N sodium hydroxide solution (1 mL) and water (3 mL) were sequentiallyadded under ice cooling, followed by stirring at room temperature. Thereaction mixture was filtered with Celite (trade name) and the filtratewas concentrated to obtain the titled compound having the followingphysical properties (2.0 g). The compound was used for the followingreaction without being purified.

TLC: Rf 0.51 (dichloromethane:methanol: 28% ammonia water=9:1:0.1);

¹H NMR (CDCl₃): δ 0.70-0.78 (m, 2H), 0.79-0.88 (m, 2H), 2.80 (s, 2H),7.07 (d, J=2.38 Hz, 1H), 7.09-7.16 (m, 1H), 7.17-7.24 (m, 1H), 7.32-7.38(m, 1H), 7.71-7.80 (m, 1H).

Example 31-(1,3-benzodioxol-5-yl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclonropane]

To an acetic acid (2 mL) solution of the compound (220 mg) prepared inExample 2, 1,3-benzodioxol-5-carboaldehyde (186 mg) was added at roomtemperature, followed by stirring at 70 to 100° C. until materialsdisappear. The reaction mixture was concentrated. The residue wasdissolved in ethyl acetate and the solution was washed in turn with anaqueous saturated sodium hydrogen carbonate solution and saturatedsaline, dried over anhydrous sodium sulfate and then concentrated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=1:2) to obtain the titled compound having the following physicalproperties (308 mg).

TLC: Rf 0.1 (hexane:ethyl acetate=1:2);

¹H NMR (CDCl₃): δ 0.70-0.80 (m, 1H), 0.81-0.91 (m, 1H), 1.37-1.50 (m,1H), 1.54-1.70 (m, 1H), 2.78 (d, J=13.17 Hz, 1H), 3.19 (d, J=13.17 Hz,1H), 5.16 (s, 1H), 5.95 (s, 2H), 6.75-6.87 (m, 3H), 6.98-7.06 (m, 1H),7.06-7.15 (m, 1H), 7.20-7.29 (m, 1H), 7.34 (d, J=7.68 Hz, 1H), 7.52 (s,1H).

Example 42-acetyl-1-(1,3-benzodioxol-5-yl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

To a pyridine (1 mL) solution of the compound (103 mg) prepared inExample 3, acetic anhydride (98 μL) was added, followed by stirring atroom temperature until materials disappear. The reaction mixture wasdiluted with ethyl acetate, washed in turn with 1N hydrochloric acid andan aqueous saturated sodium hydrogen carbonate solution, dried overanhydrous sodium sulfate and then concentrated. The residue was washedwith tert-butyl methyl ether and then collected by filtration to obtainthe titled compound having the following physical properties (83 mg).

TLC: Rf 0.10 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.73-0.86 (m, 1H), 1.03-1.14 (m, 2H), 1.54-1.67 (m,1H), 2.09 (s, 3H), 3.23 (d, J=14.64 Hz, 1H), 3.58 (d, J=14.64 Hz, 1H),5.98 (d, J=0.73 Hz, 1H), 5.99 (d, J=0.73 Hz, 1H), 6.62 (dd, J=8.05, 1.65Hz, 1H), 6.76 (d, J=1.65 Hz, 1H), 6.81 (s, 1H), 6.86 (d, J=7.87, 1 H),6.91 (m, 1H), 7.03 (m, 1H), 7.23 (d, J=7.87, 1 H), 7.28 (d, J=8.05 Hz,1H), 11.03 (s, 1H).

Example 51-(1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide

To an anhydrous tetrahydrofuran (3 mL) solution of the compound (92 mg)prepared in Example 3,1-isocyanato-3,5-dimethylbenzene (45 μL) wasadded, followed by stirring at room temperature until materialsdisappear. Hexane was added to the reaction mixture and the precipitatewas collected by filtration. The resulting product obtained byfiltration was dissolved in methanol and then concentrated to obtain thetitled compound having the following physical properties (100 mg).

TLC: Rf 0.50 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.66-0.82 (m, 1H), 0.97-1.23 (m, 2H), 1.50-1.71 (m,1H), 2.20 (s, 6H), 3.44 (d, J=14.64 Hz, 1H), 3.59 (d, J=14.64 Hz, 1H),5.98 (d, J=0.91 Hz, 1H), 5.99 (d, J=0.91 Hz, 1H), 6.60 (s, 1H), 6.65(dd, J=8.14, 1.56 Hz, 1H), 6.68 (s, 1H), 6.78 (d, J=1.46 Hz, 1H),6.84-6.96 (tn, 2H), 6.99-7.06 (m, 1H), 7.10 (s, 2H), 7.23 (d, J=7.68 Hz,1H), 7.29 (d, J=7.87 Hz, 1H), 8.43 (s, 1H), 11.04 (s, 1H).

Example 6 (1) to Example 6 (21)

Using 1H-indole-3-ylacetonitrile or alternatively a correspondingnitrile derivative thereof; a corresponding aldehyde derivative in placeof 1,3-benzodioxol-5-carboaldehyde, and acetic anhydride oralternatively a corresponding acid halide, the operation having the samepurpose as that in Example 1→Example 2→Example 3→Example 4 was conductedto obtain the following compound.

Example 6 (1)2-acetyl-1-(2,6-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.16 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.79-0.93 (m, 1H), 0.97-1.17 (m, 2H), 1.60-1.72 (m,1H), 2.09 (s, 3H), 3.38 (d, J=14.27 Hz, 1H), 3.98 (d, J=14.27 Hz, 1H),6.86-6.93 (m, 1H), 6.95 (s, 1H), 6.97-7.03 (m, 1H), 7.07 (t, J=8.60 Hz,1H), 7.20-7.29 (m, 2H), 7.33-7.48 (m, 1H), 10.88 (s, 1H).

Example 6 (2)2-acetyl-1-(3,5-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.35 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.74-0.89 (m, 1H), 1.06-1.17 (m, 2H), 1.53-1.67 (m,1H), 2.14 (s, 3H), 3.29-3.39 (m, 1H), 3.57 (d, J=14.64 Hz, 1H), 6.84 (s,1H), 6.86-6.99 (m, 3H), 7.02-7.10 (m, 1H), 7.16-7.29 (m, 2H), 7.33 (d,J=8.05 Hz, 1H), 11.10 (s, 1H).

Example 6 (3)2-acetyl-1-(2,4-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.27 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.75-0.88 (m, 1H), 1.03-1.21 (m, 2H), 1.49-1.69 (m,1H), 2.09 (s, 3H), 3.25-3.37 (m, 1H), 3.60 (d, J=14.45 Hz, 1H),6.86-7.09 (m, 4H), 7.11 (s, 1H), 7.19-7.46 (m, 3H), 10.96 (s, 1H).

Example 6 (4)2-acetyl-1-(2,3-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.24 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.72-0.92 (m, 1H), 1.02-1.21 (m, 2H), 1.53-1.70 (m,1H), 2.10 (s, 3H), 3.25-3.39 (m, 1H), 3.65 (d, J=14.82 Hz, 1H),6.74-6.84 (m, 1H), 6.88-6.97 (m, 1H), 7.00-7.09 (m, 1H), 7.09-7.20 (m,2H), 7.22-7.31 (m, 2H), 7.34-7.47 (m, 1H), 10.97 (s, 1H).

Example 6 (5)2-acetyl-1-(2,5-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.47 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.76-0.95 (m, 1H), 0.98-1.20 (m, 2H), 1.55-1.68 (m,1H), 2.10 (s, 3H), 3.24-3.41 (m, 1H), 3.66 (d, J=14.64 Hz, 1H),6.62-6.74 (m, 1H), 6.88-6.98 (m, 1H), 6.99-7.08 (m, 1H), 7.09 (s, 1H),7.17-7.48 (m, 4H), 10.96 (s, 1H).

Example 6 (6)2-acetyl-1-(3,4-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.75 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.75-0.88 (m, 1H), 1.04-1.18 (tn, 2H), 1.54-1.67 (m,1H), 2.12 (s, 3H), 3.24-3.40 (m, 1H), 3.55 (d, J=14.45 Hz, 1H), 6.84 (s,1H), 6.88-6.98 (m, 1H), 6.99-7.11 (m, 2H), 7.14-7.28 (m, 2H), 7.30 (d,J=7.87 Hz, 1H), 7.35-7.52 (m, 1H), 11.07 (s, 1H).

Example 6 (7)2-acetyl-6-chloro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.50 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.75-0.90 (m, 1H), 1.04-1.19 (m, 2H), 1.51-1.62 (m,1H), 2.12 (s, 3H), 3.23-3.41 (m, 1H), 3.54 (d, J=14.45 Hz, 1H), 6.88 (s,1H), 6.93-7.01 (m, 1H), 7.01-7.10 (m, 2H), 7.10-7.21 (m, 1H), 7.22 (d,J=1.83 Hz, 1 FI), 7.33 (d, J=8.60 Hz, 1H), 7.35-7.47 (m, 1H), 11.33 (s,1H).

Example 6 (8)2-acetyl-1-(3-fluorophenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.26 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.71-0.86 (m, 1H), 1.00-1.22 (m, 2H), 1.53-1.70 (m,1H), 2.12 (s, 3H), 3.22-3.35 (m, 1H), 3.53 (d, J=13.91 Hz, 1H),3.66-3.76 (m, 3H), 6.67 (d, J=2.20 Hz, 1H), 6.71 (dd, J=8.60, 2.20 Hz,1H), 6.86 (s, 1H), 6.93-7.01 (m, 1H), 7.05 (d, J=7.87 Hz, 1H), 7.10-7.24(m, 2H), 7.34-7.47 (m, 1H), 10.92 (s, 1H).

Example 6 (9)1-(3-fluorophenyl)-2-isobutyryl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.66 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.76-0.90 (m, 1H), 0.94-1.19 (m, 8H), 1.52-1.63 (m,1H), 2.92-3.05 (m, 1H), 142 (d, J=14.82 Hz, 1H), 3.52 (d, J=14.82 Hz,1H), 6.88-6.99 (m, 3H), 6.99-7.10 (m, 2H), 7.10-7.20 (m, 1H), 7.24 (d,J=7.87 Hz, 1H), 7.31 (d, J=8.05 Hz, 1H), 7.35-7.49 (m, 1H), 11.10 (s,1H).

Example 6 (10)2-(cyclopropylcarbonyl)-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.44 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.68-0.90 (m, 5H), 1.02-1.19 (m, 2H), 1.56-1.67 (m,1H), 2.04-2.17 (m, 1H), 3.57 (d, J=14.63 Hz, 1H), 3.69 (d, J=14.63 Hz,1H), 6.87-6.99 (m, 3H), 7.00-7.09 (m, 2H), 7.11-7.21 (m, 1H), 7.25 (d,J=8.05 Hz, 1H), 7.31 (d, J=8.05 Hz, 1H), 7.36-7.46 (m, 1H), 11.09 (s,1H).

Example 6 (11)2-benzoyl-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.42 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.41-0.59 (m, 1H), 0.57-0.75 (m, 1H), 1.03-1.30 (m,1H), 1.40-1.64 (m, 1H), 2.89 (d, J=13.72 Hz, 1H), 3.60 (d, J=13.72 Hz,1H), 6.94 (t, J=7.50 Hz, 1H), 6.99-7.29 (m, 6H), 7.29-7.56 (m, 7H),11.18 (s, 1H).

Example 6 (12)1-(3-fluorophenyl)-N,N-dimethyl-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide

TLC: Rf 0.17 (hexane:ethyl acetate=2:1);

¹H NMR (CDCl₃): δ 0.74-0.92 (m, 2H), 1.38-1.48 (m, 1H), 1.56-1.67 (m,1H), 2.87 (s, 6H), 3.07 (d, J=13.72 Hz, 1H), 3.44 (d, J=13.72 Hz, 1H),6.18 (s, 1H), 6.90-7.06 (m, 3H), 7.07-7.16 (m, 2H), 7.21-7.35 (m, 3H),7.86 (s, 1H).

Example 6 (13) methyl1-(3-fluorophenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxylate

TLC: Rf 0.53 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.72-1.00 (m, 2H), 1.00-1.14 (tn, 1H), 1.49-1.69 (m,1H), 3.37 (s, 2H), 3.68 (s, 3H), 6.44 (s, 1H), 6.88-6.97 (m, 1H),6.97-7.13 (m, 3H), 7.14-7.22 (m, 1H), 7.26 (d, J=8.05 Hz, 1H), 7.31 (d,J=7.87 Hz, 1H), 7.37-7.50 (m, 1H), 11.04 (s, 1H).

Example 6 (14)2-acetyl-1-(2,3-dihydro-1H-inden-5-yl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.70 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.73-0.89 (m, 1H), 1.01-1.16 (m, 2H), 1.52-1.66 (m,1H), 1.90-2.04 (m, 2H), 2.09 (s, 3H), 2.69-2.91 (m, 4H), 3.22 (d,J=14.45 Hz, 1H), 3.59 (d, J=14.45 Hz, 1H), 6.87 (s, 1H), 6.88-6.95 (m,1H), 6.95-7.09 (m, 3H), 7.18 (d, J=7.68 Hz, 1H), 7.23 (d, J=7.87 Hz,1H), 7.27 (d, J=8.05 Hz, 1H), 11.01 (s, 1H).

Example 6 (15)2-acetyl-6-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[3-carboline-4,1′-cyclopropane]

TLC: Rf 0.55 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.74-0.90 (m, 1H), 1.03-1.28 (m, 2H), 1.52-1.63 (m,1H), 2.12 (s, 3H), 3.22-3.34 (m, 1H), 3.54 (d, J=14.27 Hz, 1H),6.83-6.94 (m, 2H), 6.94-7.08 (m, 3H), 7.09-7.20 (m, 1H), 7.29 (dd,J=8.78, 4.57 Hz, 1H), 7.34-7.46 (m, 1H), 11.20 (s, 1H).

Example 6 (16)2-acetyl-1-(2,4-difluorophenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.53 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.71-0.89 (m, 1H), 1.02-1.25 (m, 2H), 1.50-1.65 (m,1H), 2.09 (s, 3H), 3.20-3.35 (m, 1H), 3.60 (d, J=15.00 Hz, 1H),6.79-7.07 (m, 4H), 7.10 (s, 1H), 7.20-7.34 (m, 2H), 11.07 (s, 1H).

Example 6 (17)2-acetyl-1-(3,4-difluorophenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.58 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.73-0.92 (m, 1H), 1.01-1.30 (m, 2H), 1.49-1.66 (m,1H), 2.11 (s, 3H), 3.24-3.32 (m, 1H), 3.54 (d, J=14.64 Hz, 1H), 6.84 (s,1H), 6.85-6.95 (m, 1H), 6.95-7.09 (m, 2H), 7.13-7.24 (m, 1H), 7.29 (dd,J=8.87, 4.67 Hz, 1H), 7.34-7.49 (m, 1H), 11.18 (s, 1H).

Example 6 (18)2-acetyl-1-(3-fluorophenyl)-7-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.44 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.72-0.91 (m, 1H), 0.98-1.32 (m, 2H), 1.45-1.59 (m,1H), 2.11 (s, 3H), 3.20-3.36 (m, 1H), 3.52 (d, J=14.64 Hz, 1H), 3.73 (s,3H), 6.57 (dd, J=8.78, 2.20 Hz, 1H), 6.80 (d, J=2.20 Hz, 1H), 6.83 (s,1H), 6.97 (d, J=10.06 Hz, 1H), 7.01-7.24 (m, 3H), 7.33-7.46 (m, 1H),10.88 (s, 1H).

Example 6 (19)2-acetyl-7-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.52 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.74-0.90 (m, 1H), 1.00-1.20 (m, 2H), 1.51-1.63 (m,1H), 2.11 (s, 3H), 3.19-3.39 (m, 1H), 3.54 (d, J=15.55 Hz, 1H),6.73-6.84 (m, 1H), 6.86 (s, 1H), 6.94-7.02 (m, 1H), 7.02-7.20 (m, 3H),7.23 (dd, J=8.97, 5.31 Hz, 1H), 7.32-7.48 (m, 1H), 11.20 (s, 1H).

Example 6 (20)2-acetyl-1-(3-fluorophenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.63 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.56-0.70 (m, 1H), 0.85-1.07 (m, 2H), 1.61-1.75 (tn,1H), 2.11 (s, 3H), 3.19 (d, J=14.64 Hz, 1H), 3.53 (d, J=14.64 Hz, 1H),3.80 (s, 3H), 6.48 (d, J=7.50 Hz, 1H), 6.83 (s, 1H), 6.90 (dd, J=8.05,0.73 Hz, 1H), 6.93-7.03 (m, 2H), 7.05 (d, J=7.68 Hz, 1H), 7.09-7.22 (m,1H), 7.34-7.46 (m, 1H), 11.15 (s, 1H).

Example 6 (21)2-acetyl-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.50 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.74-0.87 (m, 1H), 1.07-1.18 (m, 2H), 1.52-1.68 (m,1H), 2.12 (s, 3H), 3.29 (d, J=14.65 Hz, 1H), 3.55 (d, J=14.65 Hz, 1H),6.89 (s, 1H), 6.90-6.96 (m, 1H), 6.99 (dd, J=10.34, 1.92 Hz, 1H),7.02-7.10 (m, 2H), 7.10-7.20 (m, 1H), 7.25 (d, J=8.06 Hz, 1H), 7.31 (d,J=8.06 Hz, 1H), 7.35-7.47 (m, 1H), 11.09 (s, 1H).

Example 7 (1) to Example 7 (21)

Using 1H-indole-3-ylacetonitrile or alternatively a correspondingnitrile derivative thereof and a corresponding aldehyde derivative inplace of 1,3-benzodioxol-5-carboaldehyde, the operation having the samepurpose as that in Example 1 Example 2→Example 3→Example 5 was conductedto obtain the following compound.

Example 7 (1)1-(2,6-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide

TLC: Rf 0.39 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.72-0.86 (m, 1H), 0.91-1.12 (m, 2H), 1.56-1.68 (m,1H), 2.18 (s, 6H), 3.63 (d, J=14.64 Hz, 1H), 3.77 (d, J=14.64 Hz, 1H),6.58 (s, 1H), 6.85-6.93 (m, 1H), 6.96-7.15 (m, 6H), 7.19-7.28 (m, 2H),7.34-7.51 (m, 1H), 8.56 (s, 1H), 10.93 (s, 1H).

Example 7 (2)1-(3,5-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide

TLC: Rf 0.60 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.68-0.83 (m, 1H), 0.98-1.23 (m, 2H), 1.50-1.65 (m,1H), 2.20 (s, 6H), 3.44 (d, J=14.82 Hz, 1H), 3.67 (d, J=14.82 Hz, 1H),6.61 (s, 1H), 6.73 (s, 1H), 6.85-6.99 (m, 3H), 7.00-7.15 (m, 3H),7.15-7.29 (m, 2H), 7.33 (d, J=7.87 Hz, 1H), 8.52 (s, 1H), 11.13 (s, 1H).

Example 7 (3)1-(2,4-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide

TLC: Rf 0.53 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.63-0.84 (m, 1H), 0.91-1.15 (m, 2H), 1.45-1.68 (m,1H), 2.19 (s, 6H), 3.44 (d, J=15.00 Hz, 1H), 3.57 (d, J=15.00 Hz, 1H),6.58 (s, 1H), 6.84-6.97 (m, 2H), 6.97-7.12 (m, 5H), 7.23 (d, J=7.87 Hz,1H), 7.26-7.37 (m, 2H), 8.57 (s, 1H), 11.00 (s, 1H).

Example 7 (4)1-(2,3-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[6-carboline-4,1′-cyclopropane]-2(3H)-carboxamide

TLC: Rf 0.59 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.68-0.83 (m, 1H), 0.94-1.17 (m, 2H), 1.49-1.66 (m,1H), 2.19 (s, 6H), 3.48 (d, J=15.01 Hz, 1H), 3.59 (d, J=15.01 Hz, 1H),6.59 (s, 1H), 6.74 (t, J=6.86 Hz, 1H), 6.86-6.97 (m, 1H), 6.98-7.20 (m,5H), 7.24 (d, J=7.87 Hz, 1H), 7.29 (d, J=8.05 Hz, 1H), 7.34-7.50 (m,1H), 8.59 (s, 1H), 11.00 (s, 1H).

Example 7 (5)1-(2,5-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide

TLC: Rf 0.50 (hexane:ethyl acetate=3:1);

¹H NMR (DMSO-d₆): δ 0.70-0.84 (m, 1H), 0.95-1.17 (m, 2H), 1.53-1.66 (m,1H), 2.19 (s, 6H), 3.49 (d, J=15.01 Hz, 1H), 3.59 (d, J=15.01 Hz, 1H),6.53-6.64 (m, 2H), 6.88-6.98 (m, 1H), 7.00 (s, 1H), 7.02-7.14 (m, 3H),7.18-7.40 (m, 4H), 8.59 (s, 1H), 11.01 (s, 1H).

Example 7 (6)1-(3,4-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide

TLC: Rf 0.47 (hexane:ethyl acetate=3:1);

¹H NMR (DMSO-d₆): δ 0.69-0.83 (m, 1H), 1.00-1.21 (m, 2H), 1.53-1.65 (m,1H), 2.20 (s, 6H), 3.41 (d, J=14.82 Hz, 1H), 3.63 (d, J=14.82 Hz, 1H),6.61 (s, 1H), 6.73 (s, 1H), 6.88-6.97 (m, 1H), 7.00-7.14 (m, 4H),7.17-7.28 (m, 2H), 7.31 (d, J=8.05 Hz, 1H), 7.36-7.49 (m, 1H), 8.48 (s,1H), 11.10 (s, 1H).

Example 7 (7)6-chloro-N-(3,5-dimethylphenyl)-1-(3-fluorophenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide

TLC: Rf 0.40 (hexane:ethyl acetate=3:1);

¹H NMR (DMSO-d₆): δ 0.69-0.88 (m, 1H), 0.99-1.29 (m, 2H), 1.49-1.63 (m,1H), 2.20 (s, 6H), 3.41 (d, J=14.45 Hz, 1H), 3.64 (d, J=14.45 Hz, 1H),6.61 (s, 1H), 6.77 (s, 1H), 6.96-7.03 (m, 1H), 7.03-7.12 (m, 4H),7.12-7.21 (m, 1H), 7.22 (d, J=1.83 Hz, 1H), 7.34 (d, J=8.60 Hz, 1H),7.37-7.49 (m, 1H), 8.50 (s, 1H), 11.37 (s, 1H).

Example 7 (8)N-(3,5-dimethylphenyl)-1-(3-fluorophenyl)-6-methoxy-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide

TLC: Rf 0.24 (hexane:ethyl acetate=3:1);

¹H NMR (DMSO-d₆): δ 0.67-0.78 (m, 1H), 1.05-1.17 (m, 2H), 1.53-1.67 (m,1H), 2.21 (s, 6H), 3.40 (d, J=14.64 Hz, 1H), 3.62 (d, J=14.64 Hz, 1H),3.72 (s, 3H), 6.61 (s, 1H), 6.67 (d, J=2.20 Hz, 1H), 6.69-6.77 (m, 2H),6.96-7.04 (m, 1H), 7.06-7.19 (m, 4H), 7.21 (d, J=8.78 Hz, 1H), 7.35-7.49(m, 1H), 8.48 (s, 1H), 10.95 (s, 1H).

Example 7 (9)1-(2,3-dihydro-1H-inden-5-yl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide

TLC: Rf 0.48 (hexane:ethyl acetate=3:1);

¹H NMR (DMSO-d₆): δ 0.68-0.79 (m, 1H), 1.00-1.16 (m, 2H), 1.52-1.65 (m,1H), 1.91-2.05 (m, 2H), 2.20 (s, 6H), 2.75-2.86 (m, 4H), 3.45 (d,J=14.45 Hz, 1H), 3.58 (d, J=14.45 Hz, 1H), 6.59 (s, 1H), 6.74 (s, 1H),6.87-6.95 (m, 1H), 6.97-7.06 (m, 2H), 7.08 (s, 1H), 7.10 (s, 2H),7.16-7.31 (m, 3H), 8.41 (s, 1H), 11.02 (s, 1H).

Example 7 (10)2-acetyl-1-(3-fluorophenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.21 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.65-0.87 (m, 1H), 0.96-1.20 (m, 2H), 1.50-1.68 (m,1H), 2.11 (s, 3H), 3.18-3.29 (m, 1H), 3.50 (d, J=14.27 Hz, 1H), 3.71 (s,3H), 3.73 (s, 3H), 6.66 (s, 1H), 6.79-6.90 (m, 2H), 6.91-6.99 (m, 1H),7.00-7.09 (m, 1H), 7.08-7.22 (m, 1H), 7.31-7.48 (m, 1H), 10.76 (s, 1H).

Example 7 (11)2-acetyl-1-(2,4-difluorophenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.21 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.65-0.93 (m, 1H), 0.98-1.27 (m, 2H), 1.50-1.64 (m,1H), 2.08 (s, 3H), 3.25 (d, J=14.45 Hz, 1H), 3.55 (d, J=14.45 Hz, 1H),3.71 (s, 3H), 3.72 (s, 3H), 6.66 (s, 1H), 6.75-7.10 (m, 4H), 7.18-7.31(m, 1H), 10.62 (s, 1H).

Example 7 (12)2-acetyl-1-(2,4-difluorophenyl)-7-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.56 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.75-0.89 (m, 1H), 1.13 (m, 2H), 1.51-1.63 (m, 1H),2.08 (s, 3H), 3.19-3.37 (m, 1H), 3.59 (d, J=14.82 Hz, 1H), 6.71-6.83 (m,1H), 6.89-7.15 (m, 4H), 7.17-7.35 (m, 2H), 11.06 (s, 1H).

Example 7 (13)2-acetyl-1-(3,4-difluorophenyl)-7-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.56 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.75-0.90 (m, 1H), 1.00-1.20 (m, 2H), 1.50-1.65 (m,1H), 2.11 (s, 3H), 3.22-3.38 (m, 1H), 3.54 (d, J=14.27 Hz, 1H),6.72-6.87 (m, 2H), 6.98-7.06 (m, 1H), 7.09 (dd, J=10.06, 2.38 Hz, 1H),7.15-7.29 (m, 2H), 7.34-7.49 (m, 1H), 11.17 (s, 1H).

Example 7 (14)2-acetyl-5-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.58 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.71-0.84 (m, 1H), 0.84-0.96 (m, 1H), 1.07-1.19 (m,1H), 1.34-1.46 (m, 1H), 2.12 (s, 3H), 3.25-3.36 (m, 1H), 3.56 (dd,J=14.73, 1.19 Hz, 1H), 6.67-6.80 (m, 1H), 6.88 (s, 1H), 6.95-7.10 (m,3H), 7.11-7.23 (m, 2H), 7.35-7.49 (m, 1H), 11.50 (s, 1H).

Example 7 (15)2-acetyl-1-(2,4-difluorophenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.58 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.72-0.85 (m, 1H), 0.86-0.98 (m, 1H), 1.05-1.17 (m,1H), 1.32-1.45 (m, 1H), 2.09 (s, 3H), 3.24-3.38 (m, 1H), 3.62 (d,J=15.00 Hz, 1H), 6.67-6.79 (m, 1H), 6.91-7.09 (m, 3H), 7.09-7.19 (m,2H), 7.24-7.36 (m, 1H), 11.38 (s, 1H).

Example 7 (16)2-acetyl-1-(3,4-difluorophenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.58 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.71-0.84 (m, 1H), 0.84-0.97 (m, 1H), 1.06-1.19 (m,1H), 1.34-1.48 (m, 1H), 2.12 (s, 3H), 3.22-3.36 (tn, 1H), 3.56 (d,J=14.64 Hz, 1H), 6.67-6.80 (m, 1H), 6.85 (s, 1H), 7.00-7.11 (m, 2H),7.16 (d, J=8.05 Hz, 1H), 7.18-7.28 (m, 1H), 7.36-7.51 (m, 1H), 11.47 (s,1H).

Example 7 (17)2-acetyl-1-(3-fluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.48 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.70-0.85 (m, 1H), 1.00-1.16 (m, 2H), 1.47-1.61 (m,1H), 2.12 (s, 3 H), 3.20-3.36 (m, 1H), 3.50 (d, J=14.46 Hz, 1H), 3.86(s, 3H), 6.63 (dd, J=6.68, 1.74 Hz, 1H), 6.76-6.90 (m, 3H), 6.93 (d,J=10.06 Hz, 1H), 7.00 (d, J=7.68 Hz, 1H), 7.07-7.19 (m, 1H), 7.31-7.43(m, 1H), 11.14 (s, 1H).

Example 7 (18)2-acetyl-1-(2,4-difluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.45 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.72-0.86 (m, 1H), 1.00-1.19 (m, 2H), 1.48-1.62 (m,1H), 2.08 (s, 3H), 3.17-3.37 (m, 1H), 3.53 (d, J=14.82 Hz, 1H), 3.84 (s,3H), 6.62 (dd, J=6.95, 1.46 Hz, 1H), 6.76-6.92 (m, 3H), 6.93-7.04 (m,1H), 7.14 (s, 1H), 7.18-7.30 (m, 1H), 11.02 (s, 1H).

Example 7 (19)2-acetyl-1-(3,4-difluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.45 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.72-0.85 (m, 1H), 1.00-1.15 (m, 2H), 1.48-1.63 (m,1H), 2.11 (s, 3H), 3.18-3.36 (m, 1H), 3.50 (d, J=14.27 Hz, 1H), 3.86 (s,3H), 6.63 (dd, J=6.77, 1.83 Hz, 1H), 6.78-6.91 (m, 3H), 6.93-7.03 (m,1H), 7.08-7.20 (m, 1H), 7.31-7.46 (m, 1H), 11.12 (s, 1H).

Example 7 (20)2-acetyl-1-(3-fluorophenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[6-carboline-4,1′-cyclopropane]

TLC: Rf 0.68 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.68-0.81 (m, 1H), 1.01-1.19 (m, 2H), 1.51-1.64 (m,1H), 2.11 (s, 3H), 3.17-3.37 (m, 1H), 3.43-3.54 (m, 1H), 3.71 (s, 3H),3.84 (s, 3H), 6.25 (d, J=1.83 Hz, 1H), 6.31 (d, J=1.83 Hz, 1H), 6.84 (s,1H), 6.92 (d, J=10.06 Hz, 1H), 7.00 (d, J=7.87 Hz, 1H), 7.07-7.18 (m,1H), 7.31-7.44 (m, 1H), 10.97 (s, 1H).

Example 7 (21)2-acetyl-1-(3,4-difluorophenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.61 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.68-0.82 (m, 1H), 0.99-1.17 (m, 2H), 1.50-1.64 (m,1H), 2.11 (s, 3H), 3.25 (d, J=15.00 Hz, 1H), 3.48 (d, J=15.00 Hz, 1H),3.71 (s, 3H), 3.84 (s, 3H), 6.25 (d, J=2.01 Hz, 1H), 6.32 (d, J=2.01 Hz,1H), 6.81 (s, 1H), 6.94-7.03 (m, 1H), 7.08-7.20 (m, 1H), 7.33-7.46 (m,1H), 10.97 (s, 1H).

Example 8 3-methoxy-N-[2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide

To a mixed solution of [2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]amine(580 mg) and 3-methoxybenzoic acid (658 mg) in tetrahydrofuran (5 mL)and N,N-dimethylformamide (3 mL), 1-hydroxy-7-azabenzotriazole (HOAt)(588 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)hydrochloride (826 mg) were added, followed by stirring at roomtemperature until materials disappear. To the reaction mixture, icewater and an aqueous saturated sodium hydrogen carbonate solution weresequentially added and then extracted with ethyl acetate. The organiclayer was washed with saturated saline, dried over anhydrous sodiumsulfate and then concentrated. The residue was purified by silica gelcolumn chromatography (ethyl acetate:hexane=2:8) to obtain the titledcompound having the following physical properties (612 mg).

TLC: Rf 0.30 (hexane:ethyl acetate=1:4);

¹H NMR (CDCl₃): δ 3.09 (t, J=6.77 Hz, 2H), 3.71-3.87 (m, 5H), 6.20 (s,1H), 6.98-7.04 (m, 1H), 7.09 (dd, J=7.87, 4.76 Hz, 1H), 7.12-7.17 (m,1H), 7.17-7.21 (m, 1H), 7.24-7.32 (m, 2H), 7.97 (dd, J=7.87, 1.46 Hz,1H), 8.32 (dd, J=4.76, 1.46 Hz, 1H), 8.98 (s, 1H).

Example 98-(3-methoxyphenyl)-6,9-dihydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine

To an anhydrous acetonitrile (8.2 mL) suspension of the compound (605mg) prepared in Example 8, N,N-diethylaniline (3 μL) was added, followedby stirring at 85° C. until materials are dissolved. Then phosphorusoxychloride (1.57 g) was added, followed by stirring at 75 to 85° C.overnight. The reaction mixture was air-cooled to room temperature, andthen the solvent and excess phosphorus oxychloride were distilled off.To the residue, acetonitrile, ethyl acetate and an aqueous saturatedsodium hydrogen carbonate solution were sequentially added, followed byseparation. The aqueous layer was extracted with ethyl acetate. Thecombined organic layer was washed with saturated saline, dried overanhydrous sodium sulfate and then concentrated. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=33:67) toobtain the titled compound having the following physical properties (260mg).

TLC: Rf 0.24 (hexane:ethyl acetate=1:2);

¹H NMR (CDCl₃): δ 2.91-2.99 (m, 2H), 3.83 (s, 3H), 4.02-4.11 (m, 2H),6.97-7.04 (m, 1H), 7.05-7.13 (m, 1H), 7.34-7.42 (m, 3H), 7.61-7.69 (m,1H), 7.94 (dd, J=7.87, 1.10 Hz, 1H), 10.84 (s, 1H).

Example 108-(3-methoxyphenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine

To a methanol (5 mL) suspension of the compound (250 mg) prepared inExample 9, sodium borohydride (102 mg) was added at room temperature,followed by stirring until materials disappear. The reaction mixture wasconcentrated. To the residue, ethyl acetate and an aqueous saturatedsodium hydrogen carbonate solution were added, followed by separation.The organic layer was washed with saturated saline, dried over anhydroussodium sulfate and then concentrated. The residue was by purified bysilica gel column chromatography (hexane:ethyl acetate=1:4→ethylacetate: methanol=8:2) to obtain the titled compound having thefollowing physical properties (210 mg).

TLC: Rf 0.19 (dichloromethane:methanol=19:1);

¹H NMR (CDCl₃): δ 2.69-2.83 (m, 1H), 2.83-2.97 (m, 1H), 3.09-3.22 (m,1H), 3.35-3.47 (m, 1H), 3.77 (s, 3H), 5.19 (s, 1H), 6.83-6.95 (m, 3H),6.99 (dd, J=7.78, 4.76 Hz, 1H), 7.24-7.32 (m, 1H), 7.80 (dd, J=7.78,1.28 Hz, 1H), 7.95 (dd, J=4.76, 1.28 Hz, 1H), 8.99 (s, 1H).

Example 11N-(3,5-dimethylphenyl)-8-(3-methoxyphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

Under an argon atmosphere, to an anhydrous tetrahydrofuran (2 mL)solution of the compound (95 mg) prepared in Example 10,1-isocyanato-3,5-dimethylbenzene (40 μL) was added, followed by stirringat room temperature until materials disappear. The reaction mixture wasconcentrated and the resulting residue was washed with tert-butyl methylether and then collected by filtration to obtain the titled compoundhaving the following physical properties (126 mg).

TLC: Rf 0.25 (methylene chloride:methanol=19:1);

¹H NMR (DMSO-d₆): δ 2.20 (s, 6H), 2.66-2.98 (m, 2H), 3.03-3.23 (m, 1H),3.69 (s, 3H), 4.26 (dd, J=14.18, 4.30 Hz, 1H), 6.60 (s, 1H), 6.65 (s,1H), 6.76-6.83 (m, 2H), 6.84-6.91 (m, 1H), 7.04 (dd, J=7.87, 4.76 Hz,1H), 7.11 (s, 2H), 7.26 (t, J=8.14 Hz, 1H), 7.88 (dd, J=7.78, 1.19 Hz,1H), 8.16 (dd, J=4.76, 1.65 Hz, 1H), 8.59 (s, 1H), 11.52 (s, 1H).

Example 127-acetyl-8-(3-methoxyphenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine

To a pyridine (3 mL) solution of the compound (105 mg) prepared inExample 10, acetic anhydride (39 μL) was added, followed by stirring atroom temperature until materials disappear. The reaction mixture wasconcentrated. The resulting residue was dissolved in ethyl acetate,washed in turn with an aqueous saturated sodium hydrogen carbonatesolution and saturated saline, dried over anhydrous sodium sulfate andthen concentrated. The residue was washed with tert-butyl methyl etherand then collected by filtration to obtain the titled compound havingthe following physical properties (126 mg).

TLC: Rf 0.20 (methylene chloride:methanol=19:1);

¹H NMR (CDCl₃): δ 2.21 (s, 3H), 2.75-3.03 (m, 1H), 3.40-3.56 (m, 1H),3.75 (s, 2H), 3.92 (dd, J=14.27, 4.39 Hz, 1H), 6.81-6.89 (m, 1H),6.89-6.97 (m, 1H), 7.02 (dd, J=7.78, 4.85 Hz, 1H), 7.06 (s, 1H), 7.22(t, J=7.87 Hz, 1H), 7.80 (dd, J=7.87, 1.46 Hz, 1H), 7.98 (dd, J=4.76,1.46 Hz, 1H), 9.96 (s, 1H).

Example 13 (1) to Example 13 (10)

Using a corresponding carboxylic acid derivative in place of3-methoxybenzoic acid and 1-isocyanato-3,5-dimethylbenzene oralternatively a corresponding isocyanate derivative, the operationhaving the same purpose as that in Example 8→Example 9→Example10→Example 11 was conducted to obtain the following compound.

Example 13 (1)N-(3,5-dimethylphenyl)-8-(2-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.74 (ethyl acetate);

¹H NMR (DMSO-d₆): δ 2.19 (s, 6H), 2.67-2.94 (m, 2H), 3.05-3.24 (m, 1H),4.25 (dd, J=14.45, 4.57 Hz, 1H), 6.59 (s, 1H), 6.78-6.90 (m, 1H), 6.98(s, 1H), 7.01-7.17 (m, 4H), 7.18-7.31 (m, 1H), 7.32-7.44 (m, 1H), 7.88(dd, J=7.78, 1.19 Hz, 1H), 8.16 (dd, J=4.76, 1.65 Hz, 1H), 8.65 (s, 1H),11.42 (s, 1H).

Example 13 (2)8-(3-fluorophenyl)-N-[2-(trifluoromethyl)phenyl]-5,6,8,9-tetrahydro-7H-pyrido[4,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.55 (methylene chloride:methanol=19:1);

¹H NMR (DMSO-d₆): δ 2.73-3.00 (m, 2H), 3.07-3.23 (m, 1H), 4.24 (dd,J=14.18, 3.93 Hz, 1H), 6.62 (s, 1H), 6.98-7.11 (m, 3H), 7.11-7.22 (m,1H), 7.33-7.51 (m, 3H), 7.58-7.77 (m, 2H), 7.92 (dd, J=7.78, 1.46 Hz,1H), 8.18 (dd, J=4.76, 1.46 Hz, 1H), 8.57 (s, 1H), 11.55 (s, 1H).

Example 13 (3)8-(3-fluorophenyl)-N-(3-methoxyphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.22 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 2.73-2.97 (m, 2H), 3.07-3.22 (m, 1H), 3.70 (s, 3H),4.30 (dd, J=14.27, 4.94 Hz, 1H), 6.50-6.59 (m, 1H), 6.69 (s, 1H),6.98-7.22 (m, 7H), 7.34-7.47 (m, 1H), 7.90 (dd, J=7.68, 1.65 Hz, 1H),8.18 (dd, J=4.76, 1.65 Hz, 1H), 8.74 (s, 1H), 11.55 (s, 1H).

Example 13 (4)N-(3-chlorophenyl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.51 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 2.74-2.98 (m, 2H), 3.08-3.22 (m, 1H), 4.29 (dd,J=14.27, 4.03 Hz, 1H), 6.68 (s, 1H), 6.96-7.21 (m, 5H), 7.27 (t, J=8.05Hz, 1H), 7.36-7.49 (m, 2H), 7.67 (t, J=2.01 Hz, 1H), 7.90 (dd, J=7.87,1.46 Hz, 1H), 8.18 (dd, J=4.76, 1.46 Hz, 1H), 8.94 (s, 1H), 11.56 (s,1H).

Example 13 (5)8-(1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.70 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 2.20 (s, 6H), 2.62-2.98 (m, 2H), 3.04-3.25 (m, 1H),4.13-4.34 (m, 1H), 5.98 (d, J=0.73 Hz, 1H), 5.99 (d, J=0.73 Hz, 1H),6.60 (s, 2H), 6.63 (dd, J=8.05, 1.65 Hz, 1H), 6.80 (d, J=1.65 Hz, 1H),6.86 (d, J=8.05 Hz, 1H), 7.04 (dd, J=7.78, 4.76 Hz, 1H), 7.11 (s, 2H),7.88 (dd, J=7.78, 1.65 Hz, 1H), 8.16 (dd, J=4.76, 1.65 Hz, 1H), 8.55 (s,1H), 11.48 (s, 1H).

Example 13 (6)8-(3,5-difluorophenyl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.79 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 2.21 (s, 6H), 2.68-2.95 (m, 2H), 3.09-3.24 (m, 1H),4.24-4.35 (m, 1H), 6.61 (s, 1H), 6.63 (s, 1H), 6.87-7.00 (m, 2H), 7.06(dd, J=7.78, 4.76 Hz, 1H), 7.11 (s, 2H), 7.16-7.28 (m, 1H), 7.91 (dd,J=7.78, 1.46 Hz, 1H), 8.19 (dd, J=4.76, 1.46 Hz, 1H), 8.65 (s, 1H),11.57 (s, 1H).

Example 13 (7)8-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.50 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 2.20 (s, 6H), 2.68-2.97 (m, 2H), 3.08-3.23 (m, 1H),4.26 (dd, J=14.36, 4.67 Hz, 1H), 6.60 (s, 1H), 6.66 (s, 1H), 7.01-7.09(m, 2H), 7.11 (s, 2H), 7.26 (d, J=1.46 Hz, 1H), 7.37 (d, J=8.23 Hz, 1H),7.90 (dd, J=7.78, 1.55 Hz, 1H), 8.17 (dd, J=4.67, 1.55 Hz, 1H), 8.59 (s,1H), 11.48 (s, 1H).

Example 13 (8)N-(adamantane-1-yl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.57 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 1.60 (s, 6H), 1.95 (s, 6H), 1.99 (s, 3H), 2.59-2.86(m, 2H), 2.89-3.04 (m, 1H), 4.07 (dd, J=13.91, 4.03 Hz, 1H), 5.92 (s,1H), 6.56 (s, 1H), 6.93-7.01 (m, 1H), 7.00-7.07 (m, 2H), 7.07-7.17 (m,1H), 7.29-7.45 (m, 1H), 7.86 (dd, J=7.68, 1.56 Hz, 1H), 8.16 (dd,J=4.67, 1.56 Hz, 1H), 11.49 (s, 1H).

Example 13 (9)8-(2,3-dihydro-1H-inden-5-yl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.50 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 1.90-2.04 (m, 2H), 2.20 (s, 6H), 2.69-2.89 (m, 6H),3.06-3.21 (m, 1H), 4.23 (dd, J=13.81, 4.85 Hz, 1H), 6.59 (s, 1H), 6.67(s, 1H), 6.98 (dd, J=7.87, 1.19 Hz, 1H), 7.04 (dd, J=7.68, 4.76 Hz, 1H),7.08 (s, 1H), 7.11 (s, 2H), 7.18 (d, J=7.87 Hz, 1H), 7.87 (dd, J=7.68,1.56 Hz, 1H), 8.15 (dd, J=4.76, 1.56 Hz, 1H), 8.53 (s, 1H), 11.47 (s,1H).

Example 13 (10)N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.15 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 2.21 (s, 6H), 2.69-2.96 (m, 2H), 3.06-3.20 (m, 1H),4.28 (dd, J=14.01, 4.30 Hz, 1H), 6.61 (s, 1H), 6.67 (s, 1H), 6.99-7.20(m, 6H), 7.36-7.46 (m, 1H), 7.90 (dd, J=7.51, 1.46 Hz, 1H), 8.18 (dd,J=4.67, 1.56 Hz, 1H), 8.61 (s, 1H), 11.55 (s, 1H).

Example 14 (1) to Example 14 (5)

Using a corresponding carboxylic acid derivative in place of3-methoxybenzoic acid, the operation having the same purpose as that inExample 8→Example 9→Example 10→Example 12 was conducted to obtain thefollowing compound.

Example 14 (1)7-acetyl-8-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine

TLC: Rf 0.64 (ethyl acetate);

¹H NMR (DMSO-d₆): δ 2.16 (s, 3H), 2.75-3.00 (m, 2H), 3.29 (s, 1H), 4.16(s, 1H), 6.80-7.07 (m, 3H), 7.07-7.14 (m, 1H), 7.14-7.24 (m, 1H),7.30-7.43 (m, 1H), 7.86 (d, J=7.78, 1.65 Hz, 1H), 8.16 (dd, J=4.76, 1.65Hz, 1H), 11.05 (s, 1H).

Example 14 (2)7-acetyl-8-(1,3-benzodioxol-5-yl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine

TLC: Rf 0.32 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 2.13 (s, 3H), 2.68-2.97 (m, 2H), 3.10-3.26 (m, 1H),3.87-3.99 (m, 1H), 5.98 (d, J=0.91 Hz, 1H), 5.99 (d, J=0.91 Hz, 1H),6.58 (dd, J=7.87, 1.37 Hz, 1H), 6.71-6.77 (m, 2H), 6.84 (d, J=7.87 Hz,1H), 7.04 (dd, J=7.87, 4.76 Hz, 1H), 7.87 (dd, J=7.87, 1.10 Hz, 1H),8.15 (dd, J=4.76, 1.46 Hz, 1H), 11.45 (s, 1H).

Example 14 (3)7-acetyl-8-(3,5-difluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine

TLC: Rf 0.44 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 2.17 (s, 3H), 2.75-2.92 (m, 2H), 3.14-3.30 (m, 1H),3.96-4.09 (m, 1H), 6.77 (s, 1H), 6.83-6.94 (m, 2H), 7.06 (dd, J=7.78,4.67 Hz, 1H), 7.15-7.30 (m, 1H), 7.90 (dd, J=7.78, 1.56 Hz, 1H), 8.19(dd, J=4.67, 1.56 Hz, 1H), 11.52 (s, 1H).

Example 14 (4)7-acetyl-8-(2,2-difluoro-1,3-benzodioxol-5-yl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine

TLC: Rf 0.50 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 2.15 (s, 3H), 2.73-2.97 (m, 2H), 3.22-3.40 (m, 1H),3.91-4.06 (m, 1H), 6.80 (s, 1H), 6.98-7.10 (m, 2H), 7.19 (d, J=1.46 Hz,1H), 7.36 (d, J=8.42 Hz, 1H), 7.89 (dd, J=7.78, 1.55 Hz, 1H), 8.17 (dd,J=4.67, 1.55 Hz, 1H), 11.45 (s, 1H).

Example 14 (5)7-acetyl-8-(2,3-dihydro-1H-inden-5-yl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine

TLC: Rf 0.50 (ethyl acetate);

¹H NMR (DMSO-d₆): δ 1.88-2.04 (m, 2H), 2.12 (s, 3H), 2.71-2.91 (m, 6H),3.16-3.27 (m, 1H), 3.87-3.98 (m, 1H), 6.82 (s, 1H), 6.93 (d, J=7.68 Hz,1H), 7.00-7.08 (m, 2H), 7.16 (d, J=7.68 Hz, 1H), 7.87 (dd, J=7.69, 1.46Hz, 1H), 8.15 (dd, J=4.76, 1.46 Hz, 1H), 11.44 (s, 1H).

Example 15N-(3,5-dimethylphenyl)-8′-(3-fluorophenyl)-1′,8′-dihydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]-7′(6′H)-carboxamide

Using 1H-pyrrolo[2,3-b]pyridin-3-ylacetonitrile in place of1H-indole-3-ylacetonitrile and 3-fluorobenzoic acid in place of3-methoxybenzoic acid, the operation having the same purpose as that inExample 1→Example 2→Example 8→Example 9→Example 10→Example 5 to obtain acompound having the following physical properties.

TLC: Rf 0.31 (hexane:ethyl acetate=2:1);

¹H NMR (CDCl₃): δ 0.82-0.95 (m, 1H), 1.05-1.16 (m, 1H), 1.25-1.39 (m,1H), 1.48-1.71 (m, 1H), 2.28 (s, 6H), 3.11 (d, J=14.64 Hz, 1H), 3.82 (d,J=14.64 Hz, 1H), 6.35 (s, 1H), 6.70 (s, 1H), 6.84 (s, 1H), 6.92-7.08 (m,4H), 7.11-7.20 (m, 1H), 7.22-7.28 (m, 1H), 7.28-7.37 (m, 1H), 7.61 (dd,S=8.05, 1.46 Hz, 1H), 7.99 (dd, J=4.76, 1.46 Hz, 1H), 9.98 (s, 1H).

Example 167′-acetyl-8′-(3-fluorophenyl)-1′,6′,7′,8′-tetrahydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]

Using 1H-pyrrolo[2,3-b]pyridin-3-ylacetonitrile in place of1H-indole-3-ylacetonitrile and 3-fluorobenzoic acid in place of3-methoxybenzoic acid, the operation having the same purpose as that inExample 1→Example 2→Example 8→Example 9→Example 10→Example 4 wasconducted to obtain a compound having the following properties.

TLC: Rf 0.42 (hexane:ethyl acetate=1:2);

¹H NMR (CDCl₃): δ 0.79-0.92 (m, 1H), 0.98-1.10 (m, 1H), 1.18-1.31 (m,1H), 1.51-1.72 (m, 1H), 2.19 (s, 3H), 3.08 (d, J=14.27 Hz, 1H), 3.83 (d,J=14.27 Hz, 1H), 6.91-7.05 (m, 2H), 7.08-7.18 (m, 2H), 7.21 (d, 1H),7.24-7.37 (m, 1H), 7.61 (dd, J=7.87, 1.28 Hz, 1H), 7.89 (d, J=4.94 Hz,1H), 10.43 (s, 1H).

Example 17 1-(1-methyl-1H-indole-3-yl)cyclopropanecarbonitrile

1-(1H-indole-3-yl)cyclopropanecarbonitrile (183 mg) was dissolved inN,N-dimethylformamide (2 mL) and sodium hydride (60% in oil, 45 mg) wasadded under ice cooling, followed by stirring for 5 minutes. To thereaction solution, methyl iodide (0.07 mL) was added, followed bystirring at room temperature for one hour. To the reaction solution,water was added, followed by extraction with ethyl acetate. The organiclayer was washed with saturated saline, dried over anhydrous magnesiumsulfate and then concentrated. The residue was purified by silica gelcolumn chromatography (parallel separation purification system) toobtain the titled compound having the following physical properties (196mg).

TLC: Rf 0.30 (hexane:ethyl acetate=4:1);

¹H NMR (CDCl₃): δ 1.30-1.39 (m, 2H), 1.57-1.70 (m, 2H), 3.75 (s, 3H),6.98 (s, 1H), 7.15-7.23 (m, 1H), 7.24-7.37 (m, 2H), 7.74-7.85 (m, 1H).

Example 18 (1) to Example 18 (2)

Using the compound prepared in Example 11 in place of the compoundprepared in Example 1, 3-fluorobenzaldehyde in place of1,3-benzodioxol-5-carboaldehyde, and acetic anhydride or alteinativelymethyl chloride carbonate, the operation having the same purpose as thatin Example 2→Example 3→Example 4 was conducted to obtain the followingcompound.

Example 18 (1)2-acetyl-1-(3-fluorophenyl)-9-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.33 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.75-0.92 (m, 1H), 1.03-1.22 (m, 2H), 1.53-1.77 (m,1H), 2.11 (s, 3H), 3.21-3.32 (m, 1H), 3.39 (s, 3H), 3.52 (d, J=14.27 Hz,1H), 6.90-7.09 (m, 4H), 7.09-7.25 (m, 2H), 7.25-7.34 (m, 1H), 7.35-7.50(m, 2H).

Example 18 (2) methyl1-(3-fluorophenyl)-9-methyl-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxylate

TLC: Rf 0.60 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.77-1.01 (m, 2H), 1.01-1.14 (m, 1H), 1.60-1.71 (m,1H), 3.32-3.42 (m, 5H), 3.67 (s, 3H), 6.59 (s, 1H), 6.94-7.07 (m, 3H),7.09-7.16 (m, 1H), 7.16-7.25 (m, 1H), 7.31 (d, J=8.05 Hz, 1H), 7.37-7.48(m, 2H).

Example 198-(3-fluorophenyl)-9-methyl-6,9-dihydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine(compound A) and8-(3-fluorophenyl)-1-methyl-5,6-dihydro-1H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine(compound B)

8-(3-fluorophenyl)-5,6-dihydro-1H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine(209 mg) was dissolved in N,N-dimethylformamide (8 mL) and sodiumhydride (60% in oil, 42 mg) was added under ice cooling, followed bystirring for five minutes. To the reaction solution, methyl iodide (0.06mL) was added, followed by stirring at 0° C. for 30 minutes. To thereaction solution, water was added, followed by extraction with ethylacetate. The organic layer was washed with saturated saline, dried overanhydrous sodium sulfate and then concentrated. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=3:2→methylenechloride:methanol=85:15) to obtain the titled compound A (173 mg) andthe titled compound B (45 mg), each having the following physicalproperties.

Compound A:

TLC: Rf 0.33 (hexane:ethyl acetate=1:1);

¹H NMR (CDCl₃): δ 2.84-2.96 (m, 2H), 3.47 (s, 3H), 3.91-4.04 (m, 2H),7.09-7.23 (m, 2H), 7.29-7.39 (m, 2H), 7.39-7.49 (m, 1H), 7.96 (dd,J=7.87, 1.55 Hz, 1H), 8.44 (dd, J=4.67, 1.55 Hz, 1H).

Compound B:

TLC: Rf 0.29 (methylene chloride:methanol=9:1);

¹H NMR (CDCl₃): δ 2.92-3.06 (m, 2H), 3.97-4.16 (m, 2H), 4.34 (s, 3H),6.91 (dd, J=7.59, 6.00 Hz, 1H), 7.05-7.19 (m, 1H), 7.32-7.48 (m, 1H),7.69 (d, J=6.04 Hz, 1H), 8.02-8.21 (m, 3H).

Example 20 (1) to Example 20 (2)

Using the compound A or the compound B prepared in Example 19 in placeof the compound prepared in Example 9, the operation having the samepurpose as that in Example 10→Example 11 was conducted to obtain thefollowing compound.

Example 20 (1)N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-9-methyl-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.34 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 2.21 (s, 6H), 2.75-2.97 (m, 2H), 3.00-3.20 (m, 1H),3.43 (s, 3H), 4.13-4.40 (m, 1H), 6.62 (s, 1H), 6.80 (s, 1H), 6.96-7.26(m, 6H), 7.32-7.49 (m, 1H), 7.96 (dd, J=7.68, 1.46 Hz, 1H), 8.25 (dd,J=4.76, 1.46 Hz, 1H), 8.65 (s, 1H).

Example 20 (2)N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.41 (methylene chloride:methanol=9:1);

¹H NMR (DMSO-d₆): δ 2.20 (s, 6H), 2.73-2.84 (m, 1H), 2.85-3.01 (m, 1H),3.02-3.18 (m, 1H), 4.18 (s, 3H), 4.29-4.48 (m, 1H), 6.58 (s, 1H), 6.62(s, 1H), 6.91 (dd, J=7.32, 6.04 Hz, 1H), 7.01-7.12 (m, 1H), 7.13 (s,2H), 7.17-7.29 (m, 2H), 7.29-7.43 (m, 1H), 8.02 (d, J=6.04 Hz, 1H), 8.06(d, J=7.32 Hz, 1H), 8.58 (s, 1H).

Example 217-acetyl-8-(3-fluorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine

Using the compound A prepared in Example 19 in place of the compoundprepared in Example 9, the operation having the same purpose as that inExample 10→Example 12 was conducted to obtain the following compoundhaving the following physical properties.

TLC: Rf 0.33 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 2.15 (s, 3H), 2.69-2.99 (m, 2H), 3.15-3.30 (m, 1H),3.40 (s, 3H), 3.88-4.10 (m, 1H), 6.92-7.29 (m, 5H), 7.33-7.49 (m, 1H),7.89-8.01 (m, 1H), 8.24 (dd, J=4.76, 1.46 Hz, 1H).

Example 22N-(4,6-dimethylpyridin-2-yl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

To a tetrahydrofuran (1 mL) solution of phenyl chloroformate (157 mg), atetrahydrofuran (1 mL) solution of 6-amino-2,4-lutidine (122 mg) andtriethylamine (0.14 mL) were added under ice cooling, followed bystirring for one hour. The resulting mixture was added to atetrahydrofuran (0.5 mL) solution of8-(3-fluorophenyl)-5,6,7,8-tetrahydro-1H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine(prepared by conducting the operation having the same purpose as that inExample 8→Example 9→Example 10 using 3-fluorobenzoic acid in place of3-methoxybenzoic acid) (60 mg) and triethylamine (31 μL), followed bystirring at 70° C. for 2 hours. To the reaction mixture, an aqueoussaturated sodium hydrogen carbonate solution was added, followed byextraction with ethyl acetate. The organic layer was washed with anaqueous saturated sodium hydrogen carbonate solution and saturatedsaline, dried over anhydrous sodium sulfate and then concentrated. Theresidue was purified by silica gel column chromatography (parallelseparation purification system) and recrystallized from a mixed solventof ethyl acetate and hexane to obtain the titled compound having thefollowing physical properties (38.7 mg).

TLC: Rf 0.40 (ethyl acetate:hexane=2:1);

¹H NMR (DMSO-d₆): δ 2.22 (s, 3H), 2.33 (s, 3H), 2.68-2.81 (m, 1H),2.82-3.00 (m, 1H), 3.06-3.22 (m, 1H), 4.37 (dd, J=14.00, 4.50 Hz, 1H),6.70 (s, 2H), 7.00-7.22 (m, 4H), 7.36-7.45 (m, 1H), 7.46 (s, 1H), 7.89(dd, J=8.00, 1.50 Hz, 1H), 8.17 (dd, J=4.50, 1.50 Hz, 1H), 9.28 (s, 1H),11.53 (s, 1H).

Example 22(j)N-(2,2-difluoro-1,3-benzodioxol-5-yl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

Using (2,2-difluoro-1,3-benzodioxol-5-yl)amine in place of6-amino-2,4-lutidine, the operation having the same purpose as that inExample 22 was conducted to obtain the titled compound having thefollowing physical properties.

TLC: Rf 0.66 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 2.69-3.00 (m, 2H), 3.03-3.25 (m, 1H), 4.28 (dd,J=14.18, 4.48 Hz, 1H), 6.67 (s, 1H), 6.99-7.24 (m, 5H), 7.29 (d, J=8.78Hz, 1H), 7.35-7.47 (m, 1H), 7.61 (d, J=1.83 Hz, 1H), 7.90 (dd, J=7.96,1.56 Hz, 1H), 8.18 (dd, J=4.67, 1.56 Hz, 1H), 8.96 (s, 1H), 11.55 (s,1H).

Example 233-fluoro-N-{2-[2-(trimethylsilyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]ethyl}benzamide

A suspension of 3-iodo-4-pyridineamine (594 mg),3-fluoro-N-[4-(trimethylsilyl)-3-butynyl]benzamide (710 mg), palladiumacetate (61 mg), triphenylphosphine (142 mg), sodium acetate (443 mg)and lithium chloride (115 mg) in N,N-dimethylformamide (6 mL) andacetonitrile (3 mL) was irradiated with microwave (100 W) for 30minutes, poured into water and then extracted with ethyl acetate. Theorganic layer was washed in turn with an aqueous saturated sodiumhydrogen carbonate solution and saturated saline, dried over anhydroussodium sulfate and then concentrated. The residue was purified by silicagel column chromatography (parallel separation purification system) toobtain the titled compound having the following physical properties(404.8 mg).

TLC: Rf 0.51 (methanol: dichloromethane=1:4);

¹H NMR (CDCl₃): δ 0.41 (s, 9H), 3.23 (t, J=7.2 Hz, 2H), 3.67-3.84 (m,2H), 6.85-6.98 (m, 1H), 7.06-7.20 (m, 1H), 7.27-7.39 (m, 2H), 7.43-7.55(m, 2H), 8.20 (d, J=5.9 Hz, 1H), 8.79 (s, 1H), 9.08 (s, 1H).

Example 24 3-fluoro-N-[2-(1H-pyrrolo[3,2-c]pyridin-3-yl)-ethyl]benzamide

To a dichloromethane (10 mL) solution of the compound (400 mg) preparedin Example 23, aluminum chloride (1.51 g) was added under ice cooling,followed by stirring at room temperature overnight. The reaction mixturewas poured into a cold aqueous saturated sodium hydrogen carbonatesolution, followed by extraction with a mixed solvent of ethyl acetateand tetrahydrofuran. The organic layer was washed in turn with anaqueous saturated sodium hydrogen carbonate solution and saturatedsaline, dried over anhydrous sodium sulfate and then concentrated. Theresidue was purified by silica gel column chromatography (parallelseparation purification system) to obtain the titled compound having thefollowing physical properties (137.9 mg).

TLC: Rf 0.36 (methanol: dichloromethane=1:4);

¹H NMR (CD₃OD): δ 3.13 (t, J=7.0 Hz, 2H), 3.69 (t, J=7.0 Hz, 2H),7.19-7.31 (m, 2H), 7.39 (dd, J=6.0, 1.0 Hz, 1H), 7.41-7.52 (m, 2H),7.54-7.62 (m, 1H), 8.11 (d, J=6.0 Hz, 1H), 8.85 (d, J=1.0 Hz, 1H).

Example 25N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-Pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridine-7-carboxamide

Using the compound prepared in Example 24 in place of the compoundprepared in Example 8, the operation having the same purpose as that inExample 9→Example 10→Example 11 was conducted to obtain the titledcompound having the following physical properties.

TLC: Rf 0.28 (methylene chloride:methanol=9:1);

¹H NMR (CDCl₃): δ 2.28 (s, 6H), 2.81-2.93 (m, 1H), 2.94-3.10 (m, 1H),3.31-3.49 (m, 1H), 3.94 (dd, J=14.36, 5.03 Hz, 1H), 6.73 (s, 1H), 6.75(s, 1H), 6.93-7.04 (m, 4H), 7.08 (d, J=7.68 Hz, 1H), 7.15-7.20 (m, 1H),7.21-7.31 (m, 1H), 8.22 (dd, J=5.67, 1.10 Hz, 1H), 8.73 (s, 1H).

Example 267-acetyl-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridine

Using the compound prepared in Example 24 in place of the compoundprepared in Example 8, the operation having the same purpose as that inExample 9→Example 10→Example 12 was conducted to obtain the titledcompound having the following physical properties.

TLC: Rf 0.20 (methylene chloride:methanol=9:1);

¹H NMR (CDCl₃): δ 2.23 (s, 3H), 2.93-3.07 (m, 2H), 3.35-3.51 (m, 1H),3.88-4.01 (m, 1H), 6.93-7.12 (m, 4H), 7.18-7.41 (m, 2H), 8.25 (d, J=5.49Hz, 1H), 8.78 (s, 1H).

Example 27(+)-2-acetyl-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]and(−)-2-acetyl-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

The compound prepared in Example 6 (21) was optically resolved usingHPLC (column used: CHIRALPAK AD manufactured by Daicel ChemicalIndustries, Ltd.; development solvent: 2-propanol: hexane=1:1) to obtain(−) isomer and (+) isomer, each having the following physicalproperties.

(−) isomer:

HPLC retention time (min)=10.0;

[α]_(D)=−138.9 (MeOH, c=0.21).

(+) isomer:

HPLC retention time (min)=12.9;

[α]_(D)=+144.1 (MeOH, c=0.26).

Example 27 (1)(+)-N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamideand(−)-N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

Using the compound prepared in Example 13 (10) in place of the compoundprepared in Example 6 (21), the operation having the same purpose asthat in Example 27 was conducted to obtain the titled compound havingthe following physical properties.

(−) isomer:

[α]_(D)=−205.2 (MeOH, c=0.355).

(+) isomer:

[α]_(D)=+206.5 (MeOH, c=0.206).

Example 28(−)-2-ethanethioyl-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

The (−) isomer (40 mg) prepared in Example 27 was suspended in toluene(1.2 mL) and2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson' reagent, 49 mg) was added, followed by refluxing for onehour. The reaction solution was air-cooled and filtered, and then thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to obtain the titled compoundhaving the following physical properties (29 mg).

TLC: Rf 0.44 (hexane:ethyl acetate=4:1);

¹H NMR (CDCl₃): δ 0.75-0.95 (m, 1H), 1.00-1.14 (m, 1H), 1.34-1.48 (m,1H), 1.69-1.88 (m, 1H), 2.76 (s, 3H), 3.47 (dd, J=14.00, 1.56 Hz, 1H),3.95 (dd, J=14.00, 1.56 Hz, 1H), 6.97-7.13 (m, 2H), 7.15-7.23 (m, 1H),7.24-7.43 (m, 5H), 7.90 (s, 1H), 8.46 (s, 1H);

[α]_(D)=−379.3 (MeOH, c=0.20).

Example 28 (1)(+)-2-ethanethioyl-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Using the (+) isomer prepared in Example 27 in place of the (−) isomerprepared in Example 27, the operation having the same purpose as that inExample 28 was conducted to obtain the titled compound having thefollowing physical properties.

TLC: Rf 0.45 (hexane:ethyl acetate=4:1);

¹H NMR (CDCl₃): δ 0.74-0.92 (m, 1H), 0.99-1.16 (m, 1H), 1.34-1.48 (m,1H), 1.70-1.88 (m, 1H), 2.76 (s, 3H), 3.47 (dd, J=14.00, 1.37 Hz, 1H),3.94 (dd, J=14.00, 1.37 Hz, 1H), 6.96-7.12 (m, 2H), 7.14-7.24 (m, 1H),7.24-7.44 (m, 5H), 7.88 (s, 1H), 8.46 (s, 1H);

[α]_(D)=+358.5 (MeOH, c=0.22).

Example 29N-(3,5-dimethylphenyl)-8′-(3-fluorophenyl)-1′-methyl-1′,8′-dihydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]-7′(6′14)-carboxamide

The compound (188 mg) prepared in Example 15 was suspended in toluene (8mL) and methyl p-toluenesulfonate (0.32 mL) was added, followed byrefluxing for 2 hours. After the reaction solution was air-cooled, anaqueous saturated sodium carbonate solution was added, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate and thenconcentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:2 methylenechloride:methanol=85:15) to obtain the titled compound having thefollowing physical properties (122 mg).

TLC: Rf 0.37 (methylene chloride:methanol=9:1);

¹H NMR (DMSO-d₆): δ 0.71-0.87 (m, 1H), 0.88-1.02 (m, 1H), 1.06-1.20 (m,1H), 1.37-1.55 (m, 1H), 2.20 (s, 6H), 3.40 (d, J=14.64 Hz, 1H), 3.71 (d,J=14.64 Hz, 1H), 4.17 (s, 3H), 6.59 (s, 1H), 6.73 (s, 1H), 6.84 (dd,J=7.32, 6.04 Hz, 1H), 7.00-7.30 (m, 5H), 7.32-7.44 (m, 1H), 7.84 (d,J=7.32 Hz, 1H), 8.00 (d, J=6.04 Hz, 1H), 8.51 (s, 1H).

Example 29 (1) to Example 29 (6)

Using the (−) isomer and the (+) isomer prepared in Example 27 (1) aswell as the compounds prepared in Examples 16, 11, 13 (1) or 13 (7) inplace of the compound prepared in Example 15, the operation having thesame purpose as that in Example 29 was conducted to obtain the followingcompound.

Example 29 (1)(+)-N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]-pyridine-7-carboxamide

TLC: Rf 0.33 (methylene chloride:methanol=9:1);

¹H NMR (DMSO-d₆): δ 2.20 (s, 6H), 2.69-2.83 (m, 1H), 2.85-3.02 (m, 1H),3.02-3.21 (m, 1H), 4.18 (s, 3H), 4.28-4.48 (m, 1H), 6.58 (s, 1H), 6.62(s, 1H), 6.84-6.98 (m, 1H), 7.01-7.29 (m, 5H), 7.30-7.42 (m, 1H),7.91-8.22 (m, 2H), 8.58 (s, 1H);

[α]_(D)=+126.9 (MeOH, c=0.22).

Example 29 (2)(−)-N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.46 (methylene chloride:methanol=9:1);

¹H NMR (DMSO-d₆): δ 2.20 (s, 6H), 2.69-2.85 (m, 1H), 2.84-3.02 (m, 1H),3.02-3.20 (m, 1H), 4.18 (s, 3H), 4.26-4.47 (m, 1H), 6.58 (s, 1H), 6.62(s, 1H), 6.84-7.00 (m, 1H), 7.02-7.30 (m, 5H), 7.31-7.44 (m, 1H),7.89-8.16 (m, 2H), 8.58 (s, 1H);

[α], =−119.7 (MeOH, c=0.20).

Example 29 (3)7′-acetyl-8′-(3-fluorophenyl)-1′-methyl-1′,6′,7′,8′-tetrahydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]

TLC: Rf 0.34 (methylene chloride:methanol=9:1);

¹H NMR (CDCl₃): δ 1.60-1.96 (m, 4H), 2.02-2.19 (m, 1H), 2.23-2.38 (m,1H), 2.42-2.63 (m, 2H), 3.56-3.70 (m, 1H), 3.71-4.02 (m, 6H), 6.77 (d,J=8.97 Hz, 1H), 7.72-7.93 (m, 4H), 8.06 (dd, J=8.97, 2.20 Hz, 1H), 8.24(d, J=2.20 Hz, 1H).

Example 29 (4)N-(3,5-dimethylphenyl)-8-(3-methoxyphenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.30 (methylene chloride:methanol=9:1);

¹H NMR (DMSO-d₆): δ 2.19 (s, 6H), 2.67-2.83 (m, 1H), 2.84-3.00 (m, 1H),3.03-3.22 (m, 1H), 3.68 (s, 3H), 4.16 (s, 3H), 4.26-4.45 (m, 1H), 6.57(s, 1H), 6.60 (s, 1H), 6.81 (dd, J=7.96, 2.47 Hz, 1H), 6.85-6.97 (m,2H), 7.01 (s, 1H), 7.14 (s, 2H), 7.21 (t, J=7.96 Hz, 1H), 8.00 (d,J=6.22 Hz, 1H), 8.02-8.09 (m, J=7.32 Hz, 1H), 8.55 (s, 1H).

Example 29 (5)N-(3,5-dimethylphenyl)-8-(2-fluorophenyl)-1-methyl-1,5,6,8-tetrahydro-7H-Pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.34 (methylene chloride:methanol=9:1);

¹H NMR (DMSO-d₆): δ 2.18 (s, 6H), 2.67-2.99 (m, 2H), 3.09-3.27 (m, 1H),4.10 (s, 3H), 4.20-4.37 (m, 1H), 6.55 (s, 1H), 6.75-6.95 (m, 3H),6.97-7.07 (m, 1H), 7.09 (s, 2H), 7.12-7.22 (m, 1H), 7.24-7.38 (m, 1H),7.98 (d, J=6.04 Hz, 1H), 8.04 (d, J=6.77 Hz, 1H), 8.54 (s, 1H).

Example 29 (6)8-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide

TLC: Rf 0.36 (methylene chloride:methanol=9:1);

¹H NMR (DMSO-d₆): δ 2.20 (s, 6H), 2.66-2.85 (m, 1H), 2.86-3.02 (m, 1H),3.03-3.22 (m, 1H), 4.16 (s, 3H), 4.26-4.48 (m, 1H), 6.58 (s, 1H), 6.61(s, 1H), 6.83-6.98 (m, 1H), 7.12 (s, 2H), 7.20 (dd, J=8.23, 0.91 Hz,1H), 7.32 (d, J=8.23 Hz, 1H), 7.37 (d, J=0.91 Hz, 1H), 8.01 (d, J=6.22Hz, 1H), 8.05 (d, J=6.95 Hz, 1H), 8.55 (s, 1H).

Example 30 tert-butyl6-(3-fluorophenyl)-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[4,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxylate(compound A) and tert-butyl 2-chloro-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxylate(compound B)

An ethanol (20 mL) suspension of5-methoxy-3-(2-nitroethyl)-1H-pyrrolo[3,2-b]pyridine (1.11 g) andpalladium hydroxide/carbon (550 mg) was heated to 80° C. and an ethanol(2 mL) solution of hydrazine monohydrate (628 mg) was added dropwise,followed by stirring at 80° C. for one hour. The reaction mixture wasair-cooled to room temperature, filtered with Celite (trade name), andthen filtrate was concentrated to obtain[2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]amine. The resultingproduct was dissolved in N,N-dimethylformamide (15 mL) and3-fluorobenzoic acid (802 mg), HOAt (751 mg) and EDC hydrochloride (1.06g) were sequentially added, followed by stirring at room temperatureuntil materials disappear. To the reaction mixture, a cold aqueoussaturated sodium hydrogen carbonate solution was added, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate and thenconcentrated. The residue was dissolved in methanol (15 mL) and anaqueous 1N sodium hydroxide solution (3 mL) was added, followed bystirring for fifteen minutes. The reaction mixture was diluted withwater and then extracted with ethyl acetate. The organic layer waswashed with saturated saline, dried over anhydrous sodium sulfate andthen concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1) to obtain3-fluoro-N-[2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]benzamide.The resulting product was dissolved in anhydrous acetonitrile (76 mL)and N,N-diethylaniline (two drops) was added, followed by deaerationwith ultrasonic wave, argon substitution and further addition ofphosphorus oxychloride (2.33 mL), followed by stirring at 80 to 85° C.overnight. The reaction mixture was air-cooled to room temperature andthen concentrated. After the residue was dissolved in a mixed solvent oftetrahydrofuran and ethyl acetate, the solution was washed with anaqueous saturated sodium hydrogen carbonate solution and saturatedsaline, dried over anhydrous sodium sulfate and then concentrated toobtain a mixture of6-(3-fluorophenyl)-2-methoxy-8,9-dihydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridineand2-chloro-6-(3-fluorophenyl)-8,9-dihydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine.The mixture was dissolved in methanol (14 mL) and sodium borohydride(469 mg) was added at room temperature, followed by stirring untilmaterials disappear. To the reaction mixture, an aqueous saturatedsodium hydrogen carbonate solution was added, followed by extractionwith ethyl acetate. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate and then concentrated to obtain amixture of6-(3-fluorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridineand2-chloro-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine.The mixture was dissolved in tetrahydrofuran (13 mL) and di-tert-butyldicarbonate (960 mg) was added at room temperature, followed by stirringuntil materials disappear. The reaction mixture was concentrated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=5:1) to obtain the titled compound A (444 mg) and the titledcompound B (650 mg), each having the following physical properties.

Compound A

TLC: Rf 0.41 (hexane:ethyl acetate=3:1);

¹H NMR (CDCl₃): δ 1.50 (s, 9H), 2.79-3.21 (m, 3H), 4.00 (s, 3H), 4.29(s, 1H), 6.44 (s, 1H), 6.58 (d, J=8.60 Hz, 1H), 6.91-7.04 (m, 2H), 7.07(d, J=7.68 Hz, 1H), 7.17-7.36 (m, 1H), 7.46 (d, J=8.60 Hz, 1H), 7.65 (s,1H).

Compound B

TLC: Rf 0.28 (hexane:ethyl acetate=3:1);

¹H NMR (CDCl₃): δ 1.50 (s, 9H), 2.79-3.17 (m, 3H), 4.29 (s, 1H), 6.46(s, 1H), 6.92-7.08 (m, 3H), 7.11 (d, J=8.42 Hz, 1H), 7.19-7.39 (m, 1H),7.52 (d, J=8.42 Hz, 1H), 7.97 (s, 1H).

Example 31N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxamide

Step A:

Under an argon atmosphere, trifluoroacetic acid (1 mL) was added to thecompound A (135 mg) prepared in Example 30 at room temperature, followedby stirring until materials disappear. The reaction mixture wasconcentrated to obtain6-(3-fluorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine.

Step B:

To the compound obtained in the step A, anhydrous tetrahydrofuran (1 mL)and triethylamine (142 μL) were sequentially added and1-isocyanato-3,5-dimethylbenzene (50 μL) was added, followed by stirringuntil materials disappear. To the reaction mixture, water was added,followed by extraction with ethyl acetate. The organic layer waspurified by silica gel column chromatography (hexane:ethyl acetate=2:1)to obtain the titled compound having the following physical properties(147 mg).

TLC: Rf 0.24 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 2.21 (s, 6H), 2.74-2.93 (m, 2H), 3.02-3.20 (m, 1H),3.86 (s, 3H), 4.19-4.36 (m, 1H), 6.53 (d, J=8.60 Hz, 1H), 6.60 (s, 1H),6.66 (s, 1H), 6.96-7.04 (m, 1H), 7.05-7.20 (m, 4H), 7.33-7.46 (m, 1H),7.61 (d, J=8.60 Hz, 1H), 8.59 (s, 1H), 11.08 (s, 1H).

Example 32 tert-butyl6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxylate

The compound B (320 mg) prepared in Example 30 and 10% palladium/carbon(33 mg) were suspended in methanol (3 mL), followed by hydrogensubstitution and further stirring at room temperature until materialsdisappear. The reaction mixture was filtered with Celite (trade name)after argon substitution. The filtrate was concentrated to obtain thetitled compound. The resulting compound was used for the followingreaction without being purified.

Example 33 (1) to Example 33 (2)

Using the compound B prepared in Example 30 or the compound prepared inExample 32 in place of the compound A prepared in Example 30, theoperation having the same purpose as that in Example 31 was conducted toobtain the following compound.

Example 33 (1)2-chloro-N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxamide

TLC: Rf 0.35 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 2.21 (s, 6H), 2.75-2.97 (m, 2H), 3.03-3.25 (m, 1H),4.22-4.37 (m, 1H), 6.60 (s, 1H), 6.71 (s, 1H), 6.96-7.23 (m, 6H),7.33-7.48 (m, 1H), 7.75 (d, J=8.42 Hz, 1H), 8.62 (s, 1H), 11.54 (s, 1H).

Example 33 (2)N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxamide

TLC: Rf 0.40 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆), 2.21 (s, 6H), 2.81-2.95 (m, 2H), 3.07-3.22 (m, 1H),4.30 (dd, J=13.54, 2.56 Hz, 1H), 6.61 (s, 1H), 6.71 (s, 1H), 6.99-7.22(m, 6H), 7.36-7.47 (m, 1H), 7.68 (dd, J=8.23, 1.46 Hz, 1H), 8.29 (dd,J=4.67, 1.37 Hz, 1H), 8.62 (s, 1H), 11.26 (s, 1H).

Example 34 (1) to Example 34 (3)

Using the compound A prepared in Example 30 or alternatively thecompound B prepared in Example 30 or the compound prepared in Example32, the operation having the same purpose as that in step A of Example31→Example 4 was conducted to obtain the following compound.

Example 34 (1)7-acetyl-6-(3-fluorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine

TLC: Rf 0.66 (ethyl acetate);

¹H NMR (DMSO-d₆): δ 2.16 (s, 3H), 2.74-2.91 (m, 2H), 3.11-3.28 (m, 1H),3.86 (s, 3H), 3.91-4.04 (m, 1H), 6.52 (d, J=8.60 Hz, 1H), 6.81 (s, 1H),6.91-7.00 (m, 1H), 7.03 (d, J=7.68 Hz, 1H), 7.07-7.21 (m, 1H), 7.31-7.44(m, 1H), 7.61 (d, J=8.60 Hz, 1H), 11.06 (s, 1H).

Example 34 (2)7-acetyl-2-chloro-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine

TLC: Rf 0.68 (ethyl acetate);

¹H NMR (DMSO-d₆): δ 2.16 (s, 3H), 2.76-2.98 (m, 2H), 3.11-3.28 (m, 1H),3.94-4.08 (m, 1H), 6.85 (s, 1H), 6.92-7.07 (m, 2H), 7.08-7.23 (tn, 2H),7.33-7.48 (m, 1H), 7.75 (d, J=8.42 Hz, 1H), 11.50 (s, 1H).

Example 34 (3)7-acetyl-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine

TLC: Rf 0.23 (ethyl acetate);

¹H NMR (DMSO-d₆): δ 2.18 (s, 3H), 2.89-3.00 (m, 2H), 3.17-3.47 (m, 1H),4.00-4.12 (m, 1H), 6.94 (s, 1H), 6.97-7.04 (m, 1H), 7.06 (d, J=7.68 Hz,1H), 7.12-7.24 (m, 1H), 7.28-7.49 (m, 2H), 8.06 (d, J=7.68 Hz, 1H), 8.45(d, J=4.94 Hz, 1H), 11.93 (s, 1H).

Example 352-ethyl-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Under ice cooling, a borane-tetrahydrofuran complex (0.98M, 0.24 mL) andthe compound (26 mg) prepared in Example 6 (21) were sequentially addedto tetrahydrofuran (0.75 mL), followed by refluxing for one hour. Underice cooling, 2N hydrochloric acid (0.5 mL) was added to the reactionmixture, followed by refluxing for 30 minutes. After air cooling, anaqueous 2N sodium hydroxide solution (0.5 mL) was added to the reactionmixture, followed by extraction with ethyl acetate. The organic layerwas washed in turn with an aqueous saturated sodium hydrogen carbonatesolution and saturated saline, dried over anhydrous sodium sulfate andthen concentrated to obtain the titled compound having the followingphysical properties (25 mg).

TLC: Rf 0.28 (hexane:ethyl acetate=4:1);

¹H NMR (DMSO-d₆): δ 0.61-0.73 (m, 1H), 0.76-0.88 (m, 1H), 1.06 (t,J=7.04 Hz, 3H), 1.19-1.42 (m, 2H), 2.42 (d, J=12.99 Hz, 1H), 2.52-2.70(m, 2H), 2.82 (d, J=12.99 Hz, 1H), 4.84 (s, 1H), 6.81-6.91 (m, 1H),6.92-7.01 (m, 1H), 7.01-7.13 (m, 3H), 7.15-7.26 (m, 2H), 7.29-7.42 (m,1H), 10.52 (s, 1H).

Example 36 (1) to Example 36 (7)

Using a corresponding amine derivative in place of[2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]amine and a correspondingcarboxylic acid derivative in place of 3-methoxybenzoic acid, theoperation having the same purpose as that in Example 8→Example 9→Example10→Example 12 was conducted to obtain the following compound.

Example 36 (1)2-acetyl-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.58 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.68-1.23 (m, 3H), 1.48-1.64 (m, 1H), 2.07 and 2.29(s, 3H), 3.03-3.28 (m, 1H), 3.53-3.98 (m, 4H), 6.32-7.33 (m, 8H),10.79-10.83 (m, 1H);

Description: solid.

Example 36 (2)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.50 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.66-1.12 (m, 3H), 1.29-1.41 (m, 1H), 2.07 and 2.30(s, 3H), 3.07-3.28 (m, 1H), 3.58-3.80 (m, 1H), 3.81 and 3.95 (s, 3H),6.36-7.25 (m, 7H), 11.22 and 11.24 (s, 1H);

Description: solid.

Example 36 (3)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.71-1.36 (m, 4H), 2.07 and 2.30 (s, 3H), 3.10 and3.23 (d, J=14.8 Hz, 1H), 3.61 and 3.78 (d, J=14.8 Hz, 1H), 3.80 and 3.95(m, 3H), 6.36-7.24 (m, 6H), 11.22-11.39 (m, 1H);

Description: solid.

Example 36 (4)2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.31 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.60-1.20 (m, 3H), 1.48-1.58 (m, 1H), 2.07 and 2.29(s, 3H), 3.04-3.28 (m, 1H), 3.55-3.97 (m, 4H), 6.37-7.30 (m, 7H), 10.93(s, 1H);

Description: solid.

Example 36 (5)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.23 (ethyl acetate:hexane=1:1);

¹H NMR (DMSO-d₆): δ 0.52-1.03 (m, 3H), 1.57-1.68 (m, 1H), 2.06 and 2.28(d, 3H), 3.03-3.18 (m, 1H), 3.54-3.70 (m, 1H), 3.77-3.95 (m, 6H), 6.32and 7.05 (s, 1H), 6.46 (d, J=7.9 Hz, 1H), 6.66-6.76 (m, 1H), 6.81-6.88(m, 1H), 6.89-7.01 (m, 2H), 7.11 and 7.20 (d, J=2 Hz, 1H), 10.84-10.93(m, 1H);

Description: solid.

Example 36 (6)2-acetyl-5-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.39 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.67-1.21 (m, 3H), 1.66-1.77 (m, 1H), 2.08 and 2.30(s, 3H), 3.07-3.21 (m, 1H), 3.58-3.70 (m, 1H), 3.80 and 3.95 (s, 3H),6.40 and 7.10 (s, 1H), 6.70-6.77 (m, 1H), 6.94-6.99 (m, 1H), 7.00-7.05(m, 2H), 7.13 and 7.23 (d, J=1.8 Hz, 1H), 7.25-7.30 (m, 1H), 11.41 and11.42 (s, 1H);

Description: solid.

Example 36 (7)2-acetyl-5-chloro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.32 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.61-1.79 (m, 4H), 2.06-2.33 (m, 6H), 3.08-3.20 (m,1H), 3.58-3.71 (m, 1H), 3.75 and 3.90 (s, 3H), 6.56-6.63 (m, 1H),6.64-6.72 (m, 1H), 6.88 and 6.96 (s, 1H), 6.99-7.04 (m, 2H), 6.39 and7.11 (s, 1H), 7.21-7.28 (m, 1H), 11.34-11.43 (m, 1H);

Description: solid.

Example 37 (1) to Example 37 (21)

Using 1H-indole-3-ylacetonitrile or alternatively a correspondingnitrile derivative and a corresponding aldehyde derivative in place of1,3-benzodioxol-5-carboaldehyde, the operation having the same purposeas that in Example 1→Example 2→Example 3→Example 4 was conducted toobtain the following compound.

Example 37 (1)2-acetyl-5-fluoro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.22 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.72-1.52 (m, 4H), 2.06 and 2.17 (s, 3H), 3.31-3.52(m, 1H), 3.73 and 3.88 (s, 3H), 3.96-4.11 (m, 1H), 6.53-7.12 (m, 6H),7.27-7.47 (m, 1H), 11.03 and 11.07 (s, 1H);

Description: solid.

Example 37 (2)2-acetyl-6-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.36 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.67-1.59 (m, 4H), 2.06 and 2.29 (s, 3H), 3.09 and3.23 (d, J=14.6 Hz, 1H), 160 and 3.78 (d, J=14.6 Hz, 1H), 3.79 and 3.93(s, 3H), 6.60-6.79 (m, 2H), 6.80-7.08 (m, 4H), 6.38 and 7.11 (s, 1H),7.16-7.31 (m, 1H), 10.93 and 10.94 (s, 1H);

Description: solid.

Example 37 (3)2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.35 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.66-0.99 (m, 2H), 1.01-1.14 (m, 1H), 1.28-1.42 (m,1H), 2.07 and 2.30 (s, 3H), 3.08-3.26 (m, 1H), 3.59-3.79 (m, 1H), 3.79and 3.94 (s, 3H), 6.37-7.13 (m, 7H), 11.23 and 11.25 (m, 1H);

Description: solid.

Example 37 (4)2-acetyl-1-(5-fluoro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.47 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.53-0.72 (m, 1H), 0.76-1.09 (m, 2H), 1.47-1.84 (m,1H), 2.07 and 2.29 (m, 3H), 3.02-3.23 (m, 1H), 3.53-3.97 (m, 7H),6.23-7.41 (m, 7H), 10.87-10.94 (m, 1H);

Description: solid.

Example 37 (5)2-acetyl-1-(4-fluoro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.36 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆,100° C.): δ 0.54-0.68 (m, 1H), 0.81-1.08 (m, 2H),1.63-1.73 (m, 1H), 2.17 (s, 3H), 3.45 (s, 2H), 3.83 (s, 3H), 3.88 (s,3H), 6.48-6.52 (dd, J=7.7, 1.0 Hz, 1H), 6.61-7.00 (m, 6H), 10.54 (s,1H);

Description: solid.

Example 37 (6)2-acetyl-1-(2,4-dimethoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.39 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆) δ 0.45-0.68 (m, 1H), 0.76-1.06 (m, 2H), 1.49-1.72 (m,1H), 2.05 and 2.28 (m, 3H), 3.05-3.15 (m, 1H), 3.57-3.69 (m, 1H),3.69-3.94 (m, 9H), 6.19-7.13 (m, 7H), 10.86-10.90 (m, 1H);

Description: solid.

Example 37 (7)2-acetyl-1-(2-fluoro-6-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.27 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.56-0.74 (m, 1H), 0.75-1.05 (m, 2H), 1.68-1.87 (m,1H), 2.05 and 2.14 (s, 3H), 3.16-3.59 (m, 1H), 3.67-4.17 (m, 7H), 6.43(d, J=7.3 Hz, 1H), 6.47-7.05 (m, 5H), 7.22-7.48 (m, 1H), 10.63 and 10.69(s, 1H);

Description: solid.

Example 37 (8)2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.29 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.64-1.24 (m, 3H), 1.46-1.66 (m, 1H), 2.06 and 2.27(s, 3H), 3.04 and 3.21 (d, J=15 Hz, 1H), 3.56 and 3.75 (d, J=15 Hz, 1H),3.71 (s, 3H), 3.72 (s, 3H), 3.81 and 3.94 (s, 3H), 6.63-6.65 (m, 1H),6.66-6.73 (m, 1H), 6.80 and 6.81 (s, 1H), 6.87-6.99 (m, 1H), 6.31 and7.03 (s, 1H), 7.10 and 7.19 (d, J=2.0 Hz, 1H), 10.45 (s, 1H);

Description: solid.

Example 37 (9)2-acetyl-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.32 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.67-1.26 (m, 3H), 1.49-1.63 (m, 1H), 2.05-2.30 (m,6H), 3.14 and 3.20 (d, J=15 Hz, 1H), 3.64 and 3.77 (d, J=15 Hz, 1H),3.77 and 3.90 (s, 3H), 6.56-6.73 (m, 2H), 6.83-7.06 (m, 3H), 6.37 and7.12 (s, 1H), 7.17-7.29 (m, 2H), 10.78 (s, 1H);

Description: solid.

Example 37 (10)2-acetyl-5-fluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf O_(—)31 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆, 100° C.): δ 0.66-0.81 (m, 1H), 0.86-1.07 (m, 2H),1.36-1.47 (m, 1H), 2.07-2.33 (m, 6H), 3.27-3.75 (m, 2H), 3.86 (s, 3H),6.58-7.06 (m, 6H), 7.09-7.14 (m, 1H), 10.87 (s, 1H);

Description: solid.

Example 37 (11)2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-1,2,39-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.27 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.66-1.24 (m, 3H), 1.50-1.66 (m, 1H), 2.07 and 2.28(s, 3H), 3.07 and 3.22 (d, J=14.6 Hz, 1H), 3.54-3.97 (m, 7H), 6.62-6.75(m, 3H), 6.89-6.94 (m, 1H), 6.34 and 7.07 (s, 1H), 7.11 and 7.20 (d,J=2.0 Hz, 1H), 7.12-7.18 (m, 1H), 10.62 (s, 1H);

Description: solid.

Example 37 (12)2-acetyl-1-(4-fluoro-2-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.30 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.66-1.24 (m, 3H), 1.49-1.66 (m, 1H), 2.06 and 2.29(s, 3H), 3.08 and 3.21 (d, J=14.6 Hz, 1H), 3.55-3.94 (m, 7H), 6.60-6.77(m, 4H), 6.91-7.06 (m, 1H), 6.34 and 7.08 (s, 1H), 7.12-7.18 (m, 1H),10.63 (s, 1H);

Description: solid.

Example 37 (13)2-acetyl-6-methoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.40 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.64-1.25 (m, 3H), 1.50-1.64 (m, 1H), 2.05-2.30 (m,6H), 3.12 and 3.18 (d, J=13.2 Hz, 1H), 3.59-3.90 (m, 7H), 6.57-6.70 (m,4H), 6.85 and 6.93 (s, 1H), 6.33 and 7.08 (s, 1H), 7.11-7.16 (m, 1H),10.58-10.61 (m, 1H);

Description: solid.

Example 37 (14)2-acetyl-1-(2-fluoro-6-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.27 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.74-1.11 (m, 3H), 1.57-1.75 (m, 1H), 2.05 and 2.12(s, 3H), 3.29 and 3.52 (d, J=13.8 Hz, 1H), 3.69-4.13 (m, 7H), 6.58-6.69(m, 2H), 6.69-6.82 (m, 1H), 6.87 and 6.98 (d, J=8.1 Hz, 1H), 6.52 and6.94 (s, 1H), 7.10 (d, J=8.6 Hz, 1H), 7.25-7.45 (m, 1H), 10.38 and 10.43(s, 1H);

Description: solid.

Example 37 (15)2-acetyl-6,7-dimethoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.32 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.62-1.30 (m, 3H), 1.47-1.61 (m, 1H), 2.04-2.30 (m,6H), 3.09 and 3.17 (d, J=14.8 Hz, 1H), 3.57-3.90 (m, 10H), 6.56-6.69 (m,3H), 6.80 (s, 1H), 6.84 and 6.92 (s, 1H), 6.30 and 7.04 (s, 1H) 10.42and 10.44 (s, 1H);

Description: solid.

Example 37 (16)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.33 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.68-1.24 (m, 3H), 1.33-1.49 (m, 1H), 2.07 and 2.29(s, 3H), 2.42 (s, 3H), 3.07-3.21 (m, 1H), 3.65 (d, J=13.7 Hz, 1H), 3.81and 3.95 (s, 3H), 6.37 and 7.05 (s, 1H), 6.69-6.77 (m, 2H), 6.88-6.98(m, 2H), 7.08-7.23 (m, 2H), 10.95 and 10.96 (s, 1H);

Description: solid.

Example 37 (17)2-acetyl-1-(2-methoxy-4-methylphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.32 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.68-1.20 (m, 3H), 1.32-1.48 (m, 1H), 2.04-2.44 (m,9H), 3.11 and 3.18 (d, J=13.4 Hz, 1H), 3.62 and 3.69 (d, J=13.4 Hz, 1H),3.76 and 3.90 (s, 3H), 6.35-7.11 (m, 7H), 10.92 and 10.94 (s, 1H);

Description: solid.

Example 37 (18)2-acetyl-1-(2,3-dihydro-1-benzofuran-7-yl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.25 (hexane:ethyl acetate=1:1); ¹H NMR (DMSO-d₆): δ 0.67-1.25(m, 3H), 1.53-1.66 (m, 1H), 2.07 and 2.32 (s, 3H), 3.12-3.29 (m, 3H),3.71 (s, 3H), 3.75 and 3.80 (d, J=13.6 Hz, 1H), 4.53 (t, J=8.6 Hz, 1H),4.60-4.70 (m, 1H), 6.57-6.78 (m, 4H), 6.24 and 6.94 (s, 1H), 7.13-7.22(m, 2H), 10.63 (s, 1H);

Description: solid.

Example 37 (19)2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.68-1.22 (m, 3H), 1.32-1.49 (m, 1H), 2.07 and 2.23(s, 3H), 2.23 and 2.28 (s, 3H), 3.05-3.19 (m, 1H), 3.57-3.68 (m, 1H),3.71 (s, 3H), 3.80 and 3.94 (s, 3H), 6.34 and 7.00 (s, 1H), 6.67-6.76(m, 1H), 6.80-6.86 (m, 1H), 6.89-6.97 (m, 1H), 7.02-7.08 (m, 1H), 7.11and 7.20 (d, J=1.8 Hz, 1H), 10.72 and 10.75 (s, 1H);

Description: solid.

Example 37 (20)2-acetyl-5-fluoro-1-(2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.29 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.64-1.14 (m, 3H), 1.29-1.41 (m, 1H), 2.07 and 2.32(s, 3H), 3.11-3.26 (m, 1H), 3.62-3.78 (m, 1H), 3.78 and 3.92 (s, 3H),6.42-7.39 (m, 8H), 11.24 (s, 1H);

Description: solid.

Example 37 (21)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.27 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.53-0.72 (m, 1H), 0.80-0.91 (m, 1H), 0.92-1.04 (m,1H), 1.56-1.73 (m, 1H), 2.06 and 2.28 (s, 3H), 3.01-3.20 (m, 1H),3.55-3.70 (m, 1H), 3.75-3.94 (m, 9H), 6.31 and 7.02 (s, 1H), 6.68-6.76(m, 1H), 6.82-6.98 (m, 3H), 7.11 and 7.20 (d, J=2.0 Hz, 1H), 10.73 (s,1H);

Description: solid.

Example 38(1S)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

The compound prepared in Example 36 (2) was optically resolved usingHPLC (column used: CHIRALCEL OJ manufactured by Daicel ChemicalIndustries, Ltd.; development solvent: hexane:ethanol=85:15) to obtainthe titled compound having the following physical properties.

TLC: Rf 0.39 (ethyl acetate:hexane=2:1);

¹H NMR (CDCl₃): δ 0.62-1.43 (m, 3H), 1.59-1.75 (m, 1H), 2.21 (s, 3H),3.07-3.57 (m, 1H), 3.84-4.26 (m, 4H), 6.29-7.18 (m, 7H), 8.34 and 8.67(s, 1H);

[α]_(D)=+200.0 (CHCl₃, c=0.17);

Description: solid.

Example 38 (1)(−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Using the compound prepared in Example 36 (3) in place of the compoundprepared in Example 36 (2), the same operation as in Example 38 wasconducted to obtain the titled compound having the following physicalproperties.

TLC: Rf 0.38 (hexane:ethyl acetate=2:1);

¹H NMR (CDCl₃): δ 0.64-1.40 (m, 3H), 1.49-1.77 (m, 1H), 2.11-2.34 (m,3H), 3.05-3.57 (m, 1H), 3.73-4.36 (m, 4H), 6.23-7.16 (m, 6H), 8.33 and8.94 (s, 1H);

[α]_(D)=−148.7 (CHCl₃, c=0.18);

Description: solid.

Example 38 (2)(+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Using the compound prepared in Example 36 (3) in place of the compoundprepared in Example 36 (2), the same operation as in Example 38 wasconducted to obtain the titled compound having the following physicalproperties.

TLC: Rf 0.38 (hexane:ethyl acetate=1:2);

¹H NMR (CDCl₃): δ 0.57-1.41 (m, 3H), 1.53-1.72 (m, 1H), 2.04-2.42 (m,3H), 3.02-3.57 (m, 1H), 3.68-4.41 (xn, 4H), 6.27-7.23 (m, 6H), 8.33 and8.93 (s, 1H);

[α]_(D)=+188.9 (CHCl₃, c=0.16);

Description: solid.

Example 38 (3)(+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Using the compound prepared in Example 36 (5) in place of the compoundprepared in Example 36 (2), the same operation as in Example 38 wasconducted to obtain the titled compound having the following physicalproperties.

TLC: Rf 0.44 (hexane:ethyl acetate=2:3);

¹H NMR (CDCl₃): δ 0.52-0.77 (m, 1H), 0.80-1.26 (m, 2H), 1.76-1.99 (m,1H), 2.09-2.30 (m, 3H), 2.98-3.56 (m, 1H), 3.76-4.22 (m, 7H), 6.22-7.17(m, 7H), 8.16 and 8.36 (s, 1H);

[α]_(D)=+238.1 (CHCl₃, c=0.15);

Description: solid.

Example 38 (4)(+)-2-acetyl-1-(2-fluoro-6-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Using the compound prepared in Example 37 (7) in place of the compoundprepared in Example 36 (2), the same operation as in Example 38 wasconducted to obtain the titled compound having the following physicalproperties.

TLC: Rf 0.35 (hexane:ethyl acetate=2:3);

¹H NMR (CDCl₃): δ 0.57-2.23 (m, 7H), 3.04-4.03 (m, 7H), 4.08-4.47 (m,1H), 6.40-7.08 (m, 6H), 7.14-7.38 (m, 1H), 7.79 and 8.04 (s, 1H);

[α]_(D)=+154.9 (CHCl₃, c=0.15);

Description: solid.

Example 38 (5)(+)-2-acetyl-5-fluoro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Using the compound prepared in Example 37 (1) in place of the compoundprepared in Example 36 (2), the same operation as in Example 38 wasconducted to obtain the titled compound having the following physicalproperties.

TLC: Rf 0.32 (hexane:ethyl acetate=2:3);

¹H NMR (CDCl₃): δ 0.69-1.21 (m, 3H), 1.66-1.92 (m, 1H), 2.04-2.24 (m,3H), 3.10-3.88 (m, 1H), 3.94 (s, 3H), 4.14-4.52 (m, 1H), 6.49-7.11 (m,6H), 7.14-7.47 (m, 1H), 7.93 and 8.17 (s, 1H);

[α]_(D)=+180.8 (CHCl₃, c=0.17);

Description: solid.

Example 38 (6)(+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Using the compound prepared in Example 37 (8) in place of the compoundprepared in Example 36 (2), the same operation as in Example 38 wasconducted to obtain the titled compound having the following physicalproperties.

TLC: Rf 0.37 (hexane:ethyl acetate=1:2);

¹H NMR (CDCl₃): δ 0.68-1.81 (m, 4H), 2.12-2.24 (m, 3H), 3.08-3.54 (m,1H), 3.75-4.28 (m, 10H), 6.25-7.17 (m, 6H), 7.97 and 8.20 (s, 1H);

[α]_(D)=+146.5 (CHCl₃, c=0.16);

Description: solid.

Example 39 (1) to Example 39 (10)

Using a corresponding amine derivative in place of[2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]amine and a correspondingcarboxylic acid derivative in place of 3-methoxybenzoic acid, theoperation having the same purpose as that in Example 8→Example 9→Example10→Example 12 was conducted to obtain the following compound.

Example 39 (1)2-acetyl-5-chloro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.41 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.63-1.24 (m, 3H), 1.63-1.79 (m, 1H), 2.08 and 2.30(s, 3H), 3.09-3.19 (m, 1H), 3.59-3.69 (m, 1H), 3.79 and 3.93 (s, 3H),6.39 and 7.10 (s, 1H), 6.62-6.72 (m, 1H), 6.72-6.78 (m, 1H), 6.93-7.06(m, 3H), 7.19-7.34 (m, 1H), 11.40-11.46 (m, 1H);

Description: solid.

Example 39 (2)2-acetyl-5,6-difluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.70 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.68-1.38 (m, 4H), 2.00-2.38 (m, 3H), 3.03-3.39 (m,1H), 3.56-3.83 (m, 1H), 3.73-3.98 (m, 3H), 6.39 (s, 0.5; H), 6.61-6.81(m, 2H), 6.91-7.14 (m, 3.5; H), 11.33 (s, 1H);

Description: solid.

Example 39 (3)2-acetyl-5,6-difluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.32 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.66-1.38 (m, 4H), 2.01-2.35 (m, 6H), 3.08-3.28 (m,1H), 3.60-3.82 (m, 1H), 3.72-3.95 (m, 3H), 6.56-6.64 (m, 1H), 6.64-6.73(m, 1H), 6.87 and 6.96 (s, 1H), 7.00-7.10 (m, 2H), 6.38 and 7.12 (s,1H), 11.29 (s, 1H);

Description: solid.

Example 39 (4)2-acetyl-5-chloro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopronane]

TLC: Rf 0.50 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.67-1.21 (m, 3H), 1.69-1.88 (m, 1H), 2.07 and 2.18(s, 3H), 3.20-3.54 (m, 1H), 3.72 and 3.88 (s, 3H), 3.86 and 4.09 (d,J=14 Hz, 0.5; H), 6.53 (s, 1H), 6.69-6.86 (m, 1H), 6.86-7.07 (m, 3H),7.20-7.22 (m, 2H), 7.29-7.39 (m, 1H), 11.16-11.26 (m, 1H);

Description: solid.

Example 39 (5)2-acetyl-1-(4-chloro-2-isopropoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.33 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆, 100° C.): δ 0.72-0.87 (m, 1H), 0.93-1.07 (m, 1H),1.08-1.25 (m, 4H), 1.36 (d, J=5.9 Hz, 3H), 1.51-1.67 (m, 1H), 2.16 (s,3H), 3.52 (b, 2H), 4.61-4.90 (m, 1H), 6.72-6.97 (m, 3H), 6.97-7.07 (m,1H), 7.10 (s, 1H), 7.23 (d, J=7.9 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 10.48(s, 1H);

Description: solid.

Example 39 (6)2-acetyl-1-[4-chloro-2-(cyclopentyloxy)phenyl]-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.47 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆, 100° C.): δ 0.73-0.86 (m, 1H), 0.96-1.08 (m, 1H),1.11-1.26 (m, 1H), 1.44-2.06 (m, 9H), 2.15 (s, 3H), 3.59 (b, 2H), 4.94(s, 1H), 6.81-6.97 (m, 3H), 6.98-7.11 (m, 2H), 7.24 (d, J=7.68 Hz, 1H),7.28 (d, J=8.05 Hz, 1H), 10.49 (s, 1H);

Description: solid.

Example 39 (7)4-(2-acetyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)-3-methoxybenzonitrile

TLC: Rf 0.17 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.71-0.98 (m, 1H), 1.00-1.23 (m, 2H), 1.51-1.64 (m,1H), 2.08 and 2.30 (s, 3H), 3.00-3.34 (m, 1H), 3.53-3.84 (m, 1H), 3.87and 3.94 (s, 3H), 6.45 and 7.15 (s, 1H), 6.83-6.96 (m, 2H), 6.99-7.08(m, 1H), 7.20-7.30 (m, 2H), 7.32-7.40 (m, 1H), 7.54 and 7.63 (d, J=1.5Hz, 1H), 10.81 (s, 1H);

Description: solid.

Example 39 (8)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,7-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.28 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.66-1.15 (m, 3H), 1.25-1.38 (m, 1H), 2.07 and 2.29(s, 3H), 3.08 and 3.25 (d, J=14 Hz, 1H), 3.59 and 3.76 (d, J=14 Hz, 1H),3.80 and 3.94 (s, 3H), 6.38 and 7.08 (s, 1H), 6.70-6.82 (m, 2H),6.91-7.00 (m, 2H), 7.13 and 7.22 (d, J=2.0, 1 H), 11.34 and 11.37 (s,1H);

Description: solid.

Example 39 (9)2-acetyl-1-(4-chloro-2-methoxyphenyl)-8-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.70-1.23 (m, 3H), 1.47-1.60 (m, 1H), 2.07 and 2.31(s, 3H), 3.05 and 3.23 (d, J=15 Hz, 1H), 3.53-3.77 (d, J=15 Hz, 1H),3.80 and 3.95 (s, 3H), 6.38 and 7.18 (s, 1H), 6.63-6.69 (m, 1H),6.82-7.08 (m, 4H), 7.12 and 7.22 (d, J=2.0 Hz, 1H), 11.33 and 11.35 (s,1H);

Description: solid.

Example 39 (10)4-(2-acetyl-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)-3-methoxybenzonitrile

TLC: Rf 0.42 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.66-1.13 (m, 3H), 1.31-1.41 (m, 1H), 2.08 and 2.31(s, 3H), 3.03-3.34 (m, 1H), 3.57 and 3.78 (d, J=14.1 Hz, 1H), 3.86 and3.99 (s, 3H), 6.46 (s, 0.5; H), 6.66-6.78 (m, 1H), 6.86-6.95 (m, 1H),6.97-7.08 (m, 1H), 7.09-7.17 (m, 1.5; H), 7.32-7.40 (m, 1H), 7.55 and7.64 (d, J=1.5 Hz, 1H), 11.24 (s, 1H);

Description: solid.

Example 40 (1) to Example 40 (9)

Using 1H-indole-3-ylacetonitrile or alternatively a correspondingnitrile derivative thereof and a corresponding aldehyde derivative inplace of 1,3-benzodioxol-5-carboaldehyde, the operation having the samepurpose as that in Example 1→Example 2→4 Example 3→Example 4 wasconducted to obtain the following compound.

Example 40 (1)2-acetyl-5,6-dimethoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.20 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.52-0.70 (m, 1H), 0.79-0.90 (m, 1H), 0.91-1.02 (m,1H), 1.54-1.74 (m, 1H), 2.05 and 2.27 (s, 3H), 2.28 (s, 3H), 3.11 (m,1H), 3.59-3.70 (m, 1H), 3.76 (s, 3H), 3.83 (s, 3H), 3.89 (s, 3H), 6.31and 7.04 (s, 1H), 6.55-6.73 (m, 2H), 6.80-6.98 (m, 3H), 10.73 (s, 1H);

Description: solid.

Example 40 (2)2-acetyl-5-methoxy-1-(2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.51 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.48-1.16 (m, 3H), 1.57-1.69 (m, 1H), 2.06 and 2.30(s, 3H), 3.06-3.16 (m, 1H), 3.58-3.70 (m, 1H), 3.79 (s, 3H), 3.77 and3.91 (s, 3H), 6.37 (s, 0.5; H), 6.45 (d, J=8.1 Hz, 1H), 6.69-6.77 (m,1H), 6.79-6.89 (m, 2H), 6.89-6.98 (m, 1H), 7.02 (d, J=8.06 Hz, 0.5; H),7.07-7.14 (m, 1H), 7.23-7.36 (m, 1H), 10.87 (s, 1H);

Description: solid.

Example 40 (3)4-(2-acetyl-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)benzonitrile

TLC: Rf 0.38 (hexane:ethyl acetate=2:1);

¹H NMR (DMSO-d₆): δ 0.55-1.10 (m, 3H), 1.63-1.76 (m, 1H), 2.11 (s, 3H),3.20 (d, J=14.7 Hz, 1H), 3.46 (d, J=14.7 Hz, 1H), 3.80 (s, 3H), 6.47 (d,J=7.7 Hz, 1H), 6.86 (s, 1H), 6.87-6.91 (m, 1H), 6.98 (t, J=7.88 Hz, 1H),7.38 (d, J=8.43 Hz, 2H), 7.81 (d, J=8.43 Hz, 2H), 11.12 (s, 1H);

Description: solid.

Example 40 (4)2-acetyl-1-(2,3-dihydro-1-benzofuran-7-yl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.45 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.52-1.06 (m, 3H), 1.58-1.73 (m, 1H), 2.06 and 2.32(s, 3H), 3.11-3.29 (m, 3H), 3.66-3.77 (m, 1H), 3.79 (s, 3H), 4.47-4.71(m, 2H), 6.22 and 6.91 (s, 1H), 6.44 (d, J=7.70 Hz, 1H), 6.56-6.68 (m,1H), 6.68-6.78 (m, 1H), 6.82-6.87 (m, 1H), 6.92-6.98 (m, 1H), 7.13-7.23(m, 1H), 10.87 (s, 1H);

Description: solid.

Example 40 (5)2-acetyl-5-methoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.46 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.46-1.28 (m, 3H), 1.51-1.72 (m, 1H), 2.05 and 2.27(s, 3H), 2.29 (s, 3H), 3.05-3.15 (m, 1H), 3.58-3.69 (m, 1H), 3.79 (s,3H), 3.75 and 3.89 (s, 3H), 6.44 (d, J=7.70 Hz, 1H), 6.56-6.70 (m, 2H),6.80-6.98 (m, 3H), 6.31 and 7.06 (s, 1H), 10.84 (s, 1H);

Description: solid.

Example 40 (6)2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.46 (hexane:ethyl acetate=1:3);

¹H NMR (DMSO-d₆): δ 0.60-1.32 (m, 3H), 1.44-1.63 (m, 1H), 2.05 and 2.28(s, 3H), 2.98 and 3.16 (d, J=14.5 Hz, 1H), 3.45-3.96 (m, 10H), 6.20-6.25(m, 1H), 6.26-6.34 (m, 1.5; H), 6.61 (d, J=8.1 Hz, 1H), 6.87-6.98 (m,1H), 7.07-7.21 (m, 1.5; H), 10.72 and 10.75 (s, 1H);

Description: solid.

Example 40 (7)2-acetyl-6-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.23 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.71-1.22 (m, 3H), 1.45-1.60 (m, 1H), 2.07 and 2.29(s, 3H), 3.08 and 3.25 (d, J=14.8 Hz, 1H), 3.59 and 3.79 (d, J=14.8 Hz,1H), 3.81 and 3.94 (s, 3H), 6.39 and 7.09 (s, 1H), 6.63-6.75 (m, 1H),6.89-6.99 (m, 1H), 6.99-7.06 (m, 1H), 7.10-7.22 (m, 2H), 7.23-7.32 (m,1H), 11.05 (s, 1H);

Description: solid.

Example 40 (8)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-8-methoxy-1,2,3,9-tetrahydrospiro[0-carboline-4,1′-cyclopropane]

TLC: Rf 0.41 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.59-1.11 (m, 3H), 1.25-1.41 (m, 1H), 2.00-2.38 (m,3H), 2.93-3.25 (m, 1H), 3.43-3.76 (m, 1H), 3.75-3.97 (m, 6H), 6.25-7.35(m, 6H), 11.17-11.49 (m, 1H);

Description: solid.

Example 40 (9)2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

TLC: Rf 0.36 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.56-1.13 (m, 3H), 1.24-1.40 (m, 1H), 2.01-2.36 (m,3H), 2.98-3.25 (m, 1H), 3.46-3.75 (m, 1H), 3.74-3.97 (m, 6H), 6.29-7.22(m, 6H), 11.19-11.49 (m, 1H);

Description: solid.

Example 41 (1)(+)-2-acetyl-1-(2-fluoro-6-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Using the compound prepared in Example 37 (14) in place of the compoundprepared in Example 36 (2), the same operation as in Example 38 wasconducted to obtain the titled compound having the following physicalproperties.

TLC: Rf 0.35 (hexane:ethyl acetate=2:3);

¹H NMR (CDCl³): δ 0.74-1.23 (m, 3H), 1.70-1.92 (m, 1H), 2.06-2.26 (m,3H), 3.09-4.02 (m, 7H), 4.12-4.49 (m, 1H), 6.53-7.08 (m, 5H), 7.09-7.16(m, 1H), 7.16-7.37 (m, 1H), 7.61-8.00 (m, 1H);

[α]_(D)=+180.0 (CHCl₃, c=0.16);

Description: solid.

Example 41 (2)(+)-2-acetyl-1-(2-methoxy-4-methylphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-propane]

Using the compound prepared in Example 37 (17) in place of the compoundprepared in Example 36 (2), the same operation as in Example 38 wasconducted to obtain the titled compound having the following physicalproperties.

TLC: Rf 0.40 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.67-1.48 (m, 4H), 2.02-2.46 (m, 9H), 3.03-3.25 (m,1H), 3.57-3.73 (m, 1H), 3.73-3.92 (m, 3H), 6.36 (s, 0.5; H), 6.57-6.72(m, 2H), 6.74 (d, J=7.1 Hz, 1H), 6.84-6.98 (m, 2H), 7.04-7.14 (m, 1.5;H), 10.83-11.03 (m, 1H);

[α]_(D)=+177.4 (CHCl₃, c=0.14);

Description: solid.

Example 41 (3)(+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Using the compound prepared in Example 37 (19) in place of the compoundprepared in Example 36 (2), the same operation as in Example 38 wasconducted to obtain the titled compound having the following physicalproperties.

TLC: Rf 0.20 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.68-1.16 (m, 3H), 1.32-1.47 (m, 1H), 2.02-2.30 (m,6H), 3.06-3.19 (m, 1H), 3.58-3.68 (m, 1H), 3.72 (s, 3H), 3.80 and 3.94(s, 3H), 6.34 and 7.00 (s, 1H), 6.69 and 6.74 (d, J=8.2 Hz, 1H), 6.83and 6.85 (d, J=8.8 Hz, 1H), 6.89-6.99 (m, 1H), 7.05 and 7.06 (d, J=8.8Hz, 1H), 7.12 and 7.20 (d, J=2.0 Hz, 1H), 10.74 and 10.77 (s, 1H);

[α]_(D)=+151.1 (CHCl₃, c=0.19);

Description: solid.

Example 41 (4)(+)-2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Using the compound prepared in Example 37 (3) in place of the compoundprepared in Example 36 (2), the same operation as in Example 38 wasconducted to obtain the titled compound having the following physicalproperties.

TLC: Rf 0.26 (hexane:ethyl acetate=1:1);

¹H NMR (DMSO-d₆): δ 0.67-1.15 (m, 3H), 1.30-1.41 (m, 1H), 2.07 and 2.30(s, 3H), 3.10 and 3.24 (d, J=14.5 Hz, 1H), 3.56-3.95 (m, 4H), 6.36-7.15(m, 7H), 11.25 and 11.27 (s, 1H); [α]_(D)=+159.7 (CHCl₃, c=0.12);

Description: solid.

Example 41 (5)(+)-2-acetyl-5,6-difluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Using the compound prepared in Example 39 (3) in place of the compoundprepared in Example 36 (2), the same operation as in Example 38 wasconducted to obtain the titled compound having the following physicalproperties.

TLC: Rf 0.44 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.69-1.13 (m, 3H), 1.24-1.36 (m, 1H), 2.02-2.33 (m,6H), 3.14 and 3.24 (d, J=13.4 Hz, 1H), 3.65 and 3.77 (d, J=13.4 Hz, 1H),3.75 and 3.90 (s, 3H), 6.38 and 7.12 (s, 1H), 6.57-6.64 (m, 1H),6.65-6.72 (m, 1H), 6.87 and 6.96 (s, 1H), 7.02-7.10 (m, 2H), 11.30 (s,1H);

[α]_(D)=+157.1 (CHCl₃, c=0.12);

Description: solid.

Example 41 (6)(+)-2-acetyl-5-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]

Using the compound prepared in Example 36 (6) in place of the compoundprepared in Example 36 (2), the same operation as in Example 38 wasconducted to obtain the titled compound having the following physicalproperties.

TLC: Rf 0.51 (hexane:ethyl acetate=1:2);

¹H NMR (DMSO-d₆): δ 0.66-1.22 (m, 3H), 1.66-1.77 (m, 1H), 2.08 and 2.30(s, 3H), 3.06-3.22 (m, 1H), 3.56-3.70 (m, 1H), 3.80 and 3.95 (s, 3H),6.39 and 7.10 (s, 1H), 6.69-6.76 (m, 1H), 6.91-6.99 (m, 1H), 7.00-7.06(m, 2H), 7.14 and 7.23 (d, J=1.7 Hz, 1H), 7.23-7.30 (m, 1H), 11.42 and11.44 (s, 1H);

[α]_(D)=+166.0 (CHCl₃, c=0.14);

Description: solid.

Example 42 (1) to Example 42 (128)

It is possible to obtain the following compounds by conducting the sameoperation as in Example 27 or Example 38 using the respective racemicmodifications described in the above Examples.

Example 42 (1)

-   (+)-2-acetyl-1-(1,3-benzodioxol-5-yl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(1,3-benzodioxol-5-yl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 4)

Example 42 (2)

-   (+)-1-(1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[O-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    and    (−)-1-(1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    (optical active material of the racemic modification described in    Example 5)

Example 42 (3)

-   (+)-2-acetyl-1-(2,6-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,6-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (1))

Example 42 (4)

-   (+)-2-acetyl-1-(3,5-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3,5-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (2))

Example 42 (5)

-   (+)-2-acetyl-1-(2,4-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,4-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (3))

Example 42 (6)

-   (+)-2-acetyl-1-(2,3-clifluoropherwl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,3-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (4))

Example 42 (7)

-   (+)-2-acetyl-1-(2,5-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,5-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (5))

Example 42 (8)

-   (+)-2-acetyl-1-(3,4-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1-cyclopropane]    and    (−)-2-acetyl-1-(3,4-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (6))

Example 42 (9)

-   (+)-2-acetyl-6-chloro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-6-chloro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (7))

Example 42 (10)

-   (+)-2-acetyl-1-(3-fluorophenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3-fluorophenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cycloprooane]    (optical active material of the racemic modification described in    Example 6 (8))

Example 42 (11)

-   (+)-1-(3-fluorophenyl)-2-isobutyryl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-1-(3-fluorophenyl)-2-isobutyryl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (9))

Example 42 (12)

-   (+)-2-(cyclopropylcarbonyl)-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-(cyclopropylcarbonyl)-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (10))

Example 42 (13)

-   (+)-2-benzoyl-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-benzoyl-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (11))

Example 42 (14)

-   (+)-1-(3-fluorophenyl)-N,N-dimethyl-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    and    (−)-1-(3-fluorophenyl)-N,N-dimethyl-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    (optical active material of the racemic modification described in    Example 6 (12))

Example 42 (15)

-   (+)-methyl 1-(3-fluorophenyl)-1,9-dihydro    spiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxylate and    (−1-methyl    1-(3-fluorophenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2    (3H)-carboxylate (optical active material of the racemic    modification described in Example 6 (13))

Example 42 (16)

-   (+)-2-acetyl-1-(2,3-dihydro-1H-inden-5-yl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,3-dihydro-1H-inden-5-yl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (14))

Example 42 (17)

-   (+)-2-acetyl-6-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-6-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (15))

Example 42 (18)

-   (+)-2-acetyl-1-(2,4-difluorophenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,4-difluorophenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (16))

Example 42 (19)

-   (+)-2-acetyl-1-(3,4-difluorophenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3,4-difluorophenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (17))

Example 42 (20)

-   (+)-2-acetyl-1-(3-fluorophenyl)-7-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3-fluorophenyl)-7-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (18))

Example 42 (21)

-   (+)-2-acetyl-7-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-7-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (19))

Example 42 (22)

-   (+)-2-acetyl-1-(3-fluorophenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3-fluorophenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 6 (20))

Example 42 (23)

-   (+)-1-(2,6-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    and    (−)-1-(2,6-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    (optical active material of the racemic modification described in    Example 7 (1))

Example 42 (24)

-   (+)-1-(3,5-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    and    (−)-1-(3,5-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    (optical active material of the racemic modification described in    Example 7 (2))

Example 42 (25)

-   (+)-1-(2,4-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    and    (−)-1-(2,4-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    (optical active material of the racemic modification described in    Example 7 (3))

Example 42 (26)

-   (+)-1-(2,3-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    and    (−)-1-(2,3-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    (optical active material of the racemic modification described in    Example 7 (4))

Example 42 (27)

-   (+)-1-(2,5-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    and    (−)-1-(2,5-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    (optical active material of the racemic modification described in    Example 7 (5))

Example 42 (28)

-   (+)-1-(3,4-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    and    (−)-1-(3,4-difluorophenyl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    (optical active material of the racemic modification described in    Example 7 (6))

Example 42 (29)

-   (+)-6-chloro-N-(3,5-dimethylphenyl)-1-(3-fluorophenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    and    (−)-6-chloro-N-(3,5-dimethylphenyl)-1-(3-fluorophenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    (optical active material of the racemic modification described in    Example 7 (7))

Example 42 (30)

-   (+)-N-(3,5-dimethylphenyl)-1-(3-fluorophenyl)-6-methoxy-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    and    (−)-N-(3,5-dimethylphenyl)-1-(3-fluorophenyl)-6-methoxy-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    ((optical active material of the racemic modification described in    Example 7 (8))

Example 42 (31)

-   (+)-1-(2,3-dihydro-1H-inden-5-yl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    and    (−)-1-(2,3-dihydro-1H-inden-5-yl)-N-(3,5-dimethylphenyl)-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxamide    (optical active material of the racemic modification described in    Example 7 (9))

Example 42 (32)

-   (+)-2-acetyl-1-(3-fluorophenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3-fluorophenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 7 (10))

Example 42 (33)

-   (+)-2-acetyl-1-(2,4-difluorophenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,4-difluorophenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 7 (11))

Example 42 (34)

-   (+)-2-acetyl-1-(2,4-difluorophenyl)-7-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,4-difluorophenyl)-7-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 7 (12))

Example 42 (35)

-   (+)-2-acetyl-1-(3,4-difluorophenyl)-7-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3,4-difluorophenyl)-7-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 7 (13))

Example 42 (36)

-   (+)-2-acetyl-5-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-5-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 7 (14))

Example 42 (37)

-   (+)-2-acetyl-1-(2,4-difluorophenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,4-difluorophenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 7 (15))

Example 42 (38)

-   (+)-2-acetyl-1-(3,4-difluorophenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3,4-difluorophenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 7 (16))

Example 42 (39)

-   (+)-2-acetyl-1-(3-fluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3-fluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 7 (17))

Example 42 (40)

-   (+)-2-acetyl-1-(2,4-difluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,4-difluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[6-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 7 (18))

Example 42 (41)

-   (+)-2-acetyl-1-(3,4-difluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3,4-difluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[6-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 7 (19))

Example 42 (42)

-   (+)-2-acetyl-1-(3-fluorophenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3-fluorophenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 7 (20))

Example 42 (43)

-   (+)-2-acetyl-1-(3,4-difluorophenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3,4-difluorophenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 7 (21))

Example 42 (44)

-   (+)-N-(3,5-dimethylphenyl)-8-(3-methoxyphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-N-(3,5-dimethylphenyl)-8-(3-methoxyphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 11)

Example 42 (45)

-   (+)-7-acetyl-8-(3-methoxyphenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    and    (−)-7-acetyl-8-(3-methoxyphenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    (optical active material of the racemic modification described in    Example 12)

Example 42 (46)

-   (+)-N-(3,5-dimethylphenyl)-8-(2-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-N-(3,5-dimethylphenyl)-8-(2-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    (optical active material of the racemic modification described in    Example 13 (1))

Example 42 (47)

-   (+)-8-(3-fluorophenyl)-N-[2-(trifluoromethyl)phenyl]-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-8-(3-fluorophenyl)-N-[2-(trifluoromethyl)phenyl]-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 13 (2))

Example 42 (48)

-   (+)-8-(3-fluorophenyl)-N-(3-methoxyphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-8-(3-fluorophenyl)-N-(3-methoxyphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 13 (3))

Example 42 (49)

-   (+)-N-(3-chlorophenyl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-N-(3-chlorophenyl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 13 (4))

Example 42 (50)

-   (+)-8-(1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-8-(1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 13 (5))

Example 42 (51)

-   (+)-8-(3,5-difluorophenyl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-8-(3,5-difluorophenyl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 13 (6))

Example 42 (52)

-   (+)-8-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-8-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 13 (7))

Example 42 (53)

-   (+)-N-(adamantane-1-yl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-N-(adamantane-1-yl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 13 (8))

Example 42 (54)

-   (+)-8-(2,3-dihydro-1H-inden-5-yl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-8-(2,3-dihydro-1H-inden-5-yl)-N-(3,5-dimethylphenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 13 (9))

Example 42 (55)

-   (+)-7-acetyl-8-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    and    (−)-7-acetyl-8-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    (optical active material of the racemic modification described in    Example 14 (1))

Example 42 (56)

-   (+)-7-acetyl-8-(1,3-benzodioxol-5-yl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    and    (−)-7-acetyl-8-(1,3-benzodioxol-5-yl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    (optical active material of the racemic modification described in    Example 14 (2))

Example 42 (57)

-   (+)-7-acetyl-8-(3,5-difluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    and    (−)-7-acetyl-8-(3,5-difluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    (optical active material of the racemic modification described in    Example 14 (3))

Example 42 (58)

-   (+)-7-acetyl-8-(2,2-difluoro-1,3-benzodioxol-5-yl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    and    (−)-7-acetyl-8-(2,2-difluoro-1,3-benzodioxol-5-yl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    (optical active material of the racemic modification described in    Example 14 (4))

Example 42 (59)

-   (+)-7-acetyl-8-(2,3-dihydro-1H-inden-5-yl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    and    (−)-7-acetyl-8-(2,3-dihydro-1H-inden-5-yl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    (optical active material of the racemic modification described in    Example 14 (5))

Example 42 (60)

-   (+)-N-(3,5-dimethylphenyl)-8′-(3-fluorophenyl)-1′,8′-dihydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]-7′(6′H)-carboxamide    and    (−)-N-(3,5-dimethylphenyl)-8′-(3-fluorophenyl)-1′,8′-dihydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]-7′(6′H)-carboxamide    (optical active material of the racemic modification described in    Example 15)

Example 42 (61)

-   (+)-7′-acetyl-8′-(3-fluorophenyl)-1′,6′,7′,8′-tetrahydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]-pyrrolo[2,3-b]pyridine]    and    (−)-7′-acetyl-8′-(3-fluorophenyl)-1′,6′,7′,8′-tetrahydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]    (optical active material of the racemic modification described in    Example 16)

Example 42 (62)

-   (+)-2-acetyl-1-(3-fluorophenyl)-9-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(3-fluorophenyl)-9-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 18 (1))

Example 42 (63)

-   (+)-methyl    1-(3-fluorophenyl)-9-methyl-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxylate    and (−)-methyl    1-(3-fluorophenyl)-9-methyl-1,9-dihydrospiro[β-carboline-4,1′-cyclopropane]-2(3H)-carboxylate    (optical active material of the racemic modification described in    Example 18 (2))

Example 42 (64)

-   (+)-N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-9-methyl-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-9-methyl-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 20 (1))

Example 42 (65)

-   (+)-N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-N-(3,5-dimethylphenyl)-8-(3-fluorophenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 20 (2))

Example 42 (66)

-   (+)-7-acetyl-8-(3-fluorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-pyrido-[4′,3′:4,5]pyrrolo[2,3-b]pyridine    and    (−)-7-acetyl-8-(3-fluorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine    (optical active material of the racemic modification described in    Example 21)

Example 42 (67)

-   (+)-N-(4,6-dimethylpyridin-2-yl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-N-(4,6-dimethylpyridin-2-yl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 22)

Example 42 (68)

-   (+)-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-8-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 22 (1))

Example 42 (69)

-   (+)-N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridine-7-carboxamide    and    (−)-N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 25)

Example 42 (70)

-   (+)-7-acetyl-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridine    and    (−)-7-acetyl-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridine    (optical active material of the racemic modification described in    Example 26)

Example 42 (71)

-   (+)-N-(3,5-dimethylphenyl)-8′-(3-fluorophenyl)-1′-methyl-1′,8′-dihydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]-7′(6′H)-carboxamide    and    (−)-N-(3,5-dimethylphenyl)-8′-(3-fluorophenyl)-1′-methyl-1′,8′-dihydro    spiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]-7′(6′H)-carboxamide    (optical active material of the racemic modification described in    Example 29)

Example 42 (72)

-   (+)-7′-acetyl-8′-(3-fluorophenyl)-1′-methyl-1′,6′,7′,8′-tetrahydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]    and    (−)-7′-acetyl-8′-(3-fluorophenyl)-1′-methyl-1′,6′,7′,8′-tetrahydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine]    (optical active material of the racemic modification described in    Example 29 (3))

Example 42 (73)

-   (+)-N-(3,5-dimethylphenyl)-8-(3-methoxyphenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-N-(3,5-dimethylphenyl)-8-(3-methoxyphenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 29 (4))

Example 42 (74)

-   (+)-N-(3,5-dimethylphenyl)-8-(2-fluorophenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-N-(3,5-dimethylphenyl)-8-(2-fluorophenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 29 (5))

Example 42 (75)

-   (+)-8-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    and    (−)-8-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(3,5-dimethylphenyl)-1-methyl-1,5,6,8-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 29 (6))

Example 42 (76)

-   (+)-N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxamide    and    (−)-N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 31)

Example 42 (77)

-   (+)-2-chloro-N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxamide    and    (−)-2-chloro-N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 33 (1))

Example 42 (78)

-   (+)-N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxamide    and    (−)-N-(3,5-dimethylphenyl)-6-(3-fluorophenyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine-7-carboxamide    (optical active material of the racemic modification described in    Example 33 (2))

Example 42 (79)

-   (+)-7-acetyl-6-(3-fluorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine    and    (−)-7-acetyl-6-(3-fluorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine    (optical active material of the racemic modification described in    Example 34 (1))

Example 42 (80)

-   (+)-7-acetyl-2-chloro-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine    and    (−)-7-acetyl-2-chloro-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine    (optical active material of the racemic modification described in    Example 34 (2))

Example 42 (81)

-   (+)-7-acetyl-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine    and    (−)-7-acetyl-6-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[3,2-b]pyridine    (optical active material of the racemic modification described in    Example 34 (3))

Example 42 (82)

-   (+)-2-ethyl-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-ethyl-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 35)

Example 42 (83)

-   (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[3-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 36 (1))

Example 42 (84)

-   (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 36 (2))

Example 42 (85)

-   (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    ((−) isomer of the racemic modification described in Example 36 (4))

Example 42 (86)

-   (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]((−)    isomer of the racemic modification described in Example 36 (5))

Example 42 (87)

-   (−)-2-acetyl-5-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]((−)    isomer of the racemic modification described in Example 36 (6))

Example 42 (88)

-   (+)-2-acetyl-5-chloro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-5-chloro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 36 (7))

Example 42 (89)

-   (−)-2-acetyl-5-fluoro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    ((−) isomer of the racemic modification described in Example 37 (1))

Example 42 (90)

-   (+)-2-acetyl-6-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-6-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (2))

Example 42 (91)

-   (−)-2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    ((−) isomer of the racemic modification described in Example 37 (3))

Example 42 (92)

-   (+)-2-acetyl-1-(5-fluoro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(5-fluoro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (4))

Example 42 (93)

-   (+)-2-acetyl-1-(4-fluoro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(4-fluoro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (5))

Example 42 (94)

-   (+)-2-acetyl-1-(2,4-dimethoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,4-dimethoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (6))

Example 42 (95)

-   (−)-2-acetyl-1-(2-fluoro-6-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]((−)    isomer of the racemic modification described in Example 37 (7))

Example 42 (96)

-   (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]((−)    isomer of the racemic modification described in Example 37 (8))

Example 42 (97)

-   (+)-2-acetyl-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (9))

Example 42 (98)

-   (+)-2-acetyl-5-fluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-5-fluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (10))

Example 42 (99)

-   (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (11))

Example 42 (100)

-   (+)-2-acetyl-1-(4-fluoro-2-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(4-fluoro-2-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (12))

Example 42 (101)

-   (+)-2-acetyl-6-methoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-6-methoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (13))

Example 42 (102)

-   (−)-2-acetyl-1-(2-fluoro-6-methoxyphenyl)-6-methoxy-tetrahydrospiro[β-carboline-4,1′-cyclopropane]((−)    isomer of the racemic modification described in Example 37 (14))

Example 42 (103)

-   (+)-2-acetyl-6,7-dimethoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-6,7-dimethoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (15))

Example 42 (104)

-   (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (16))

Example 42 (105)

-   (−)-2-acetyl-1-(2-methoxy-4-methylphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]((−)    isomer of the racemic modification described in Example 37 (17))

Example 42 (106)

-   (+)-2-acetyl-1-(2,3-dihydro-1-benzofuran-7-yl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,3-dihydro-1-benzofuran-7-yl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (18))

Example 42 (107)

-   (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]((−)    isomer of the racemic modification described in Example 37 (19))

Example 42 (108)

-   (+)-2-acetyl-5-fluoro-1-(2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-5-fluoro-1-(2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (20))

Example 42 (109)

-   (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 37 (21))

Example 42 (110)

-   (+)-2-acetyl-5-chloro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-5-chloro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 39 (1))

Example 42 (111)

-   (+)-2-acetyl-5,6-difluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-5,6-difluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[0-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 39 (2))

Example 42 (112)

-   (−)-2-acetyl-5,6-difluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]((−)    isomer of the racemic modification described in Example 39 (3))

Example 42 (113)

-   (+)-2-acetyl-5-chloro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-5-chloro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 39 (4))

Example 42 (114)

-   (+)-2-acetyl-1-(4-chloro-2-isopropoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(4-chloro-2-isopropoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 39 (5))

Example 42 (115)

-   (+)-2-acetyl-1-[4-chloro-2-(cyclopentyloxy)phenyl]-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-[4-chloro-2-(cyclopentyloxy)phenyl]-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 39 (6))

Example 42 (116)

-   (+)-4-(2-acetyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)-3-methoxybenzonitrile    and    (−)-4-(2-acetyl-1,2,3,9-tetrahydrospiro[β-carbonline-4,1′-cyclopropane]-1-yl)-3-methoxybenzonitrile    (optical active material of the racemic modification described in    Example 39 (7))

Example 42 (117)

-   (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,7-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,7-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 39 (8))

Example 42 (118)

-   (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-8-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-8-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 39 (9))

Example 42 (119)

-   (+)-4-(2-acetyl-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)-3-methoxybenzonitrile    and    (−)-4-(2-acetyl-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)-3-methoxybenzonitrile    (optical active material of the racemic modification described in    Example 39 (10))

Example 42 (120)

-   (+)-2-acetyl-5,6-dimethoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-5,6-dimethoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 40 (1))

Example 42 (121)

-   (+)-2-acetyl-5-methoxy-1-(2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-5-methoxy-1-(2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[6-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 40 (2))

Example 42 (122)

-   (+)-4-(2-acetyl-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)benzonitrile    and    (−)-4-(2-acetyl-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)benzonitrile    (optical active material of the racemic modification described in    Example 40 (3))

Example 42 (123)

-   (+)-2-acetyl-1-(2,3-dihydro-1-benzofuran-7-yl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(2,3-dihydro-1-benzofuran-7-yl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 40 (4))

Example 42 (124)

-   (+)-2-acetyl-5-methoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-5-methoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 40 (5))

Example 42 (125)

-   (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 40 (6))

Example 42 (126)

-   (+)-2-acetyl-6-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-6-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-]cyclopropane]    (optical active material of the racemic modification described in    Example 40 (7))

Example 42 (127)

-   (+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 40 (8))

Example 42 (128)

-   (+)-2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    and    (−)-2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (optical active material of the racemic modification described in    Example 40 (9))

BIOLOGICAL EXAMPLES

It was proved by the following experiments that the compound of thepresent invention has the effect of the present invention, particularlyan antistress effect. The methods for experiments will be shown below,but are not limited thereto. PK11195 described in the following Examplesis described in Eur. J. Pharmacol., 119, pp. 153-167, 1985 as an MBRselective ligand(1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide).Also, CB34 is described in British Journal of Pharmacology, 127, pp.177-187, 1999 as an MBR selective agonist[5,7-dichloro-2-(4-chlorophenyl)-3-dipropylaminocarbonylimidazo[1,2-a]pyridine.

Biological Example 1 Receptor Binding Experiment

Affinity of the compound of the present invention for MBR was measuredusing a rat membrana cerebri specimen. The measuring method of thepresent invention has improved measurement accuracy and measurementsensitivity so as to evaluate the compound of the present invention asfollows. A Wistar male rat was decapitated and the whole brain wasextirpated, and then the cerebellum was removed. For the rat membranacerebri specimen used in the binding experiment, 50 mmol/L of anice-cold Iris-hydrochloric acid buffer (pH 7.4) was added and it washomogenized and centrifuged. After the resulting deposit was washed, itwas resuspended to be prepared to about 1 mg/ml. The binding experimentwas conducted using [³H]PK11195 as an MBR selective ligand.

In the case of calculating the all binding amount in a saturationexperiment, the membrane specimen, [³H]PK11195 at severalconcentrations, dimethyl sulfoxide (DMSO) in a final concentration of0.5 vol %, and 50 mmol/L of a tris-hydrochloric acid buffer (pH 7.4)were mixed (all amount 200 μl), followed by incubation at roomtemperature for one hour. In the case of calculating the nonspecificbinding amount, [³H]PK11195 in a final concentration of 20 ptrnol/L wasadded instead of DMSO, followed by incubation for one hour. They wererapidly filtered on a GF/B filter pretreated with 0.3% polyethylenimineusing a harvester, and washed with 50 mmol/L of a tris-hydrochloric acidbuffer (pH 7.4) twice. After the filter was dried, radioactivity wasmeasured by a liquid scintillation counter. With respect to the dataobtained in the binding experiment, a Scatchard analysis was performedusing analysis software KELL (Ver.6 BIOSOFT) to calculate a dissociationconstant (K_(D) value).

In the case of calculating the all binding amount in a competitionexperiment, the membrane specimen, [³H]PK11195 in a final concentrationof 0.5 or 1 nmol/L, DMSO in a final concentration of 0.5 vol %, and 50mmol/L of a tris-hydrochloric acid buffer (pH 7.4) were mixed (allamount 200 μl), followed by incubation at room temperature for one hour.In the case of calculating the nonspecific binding amount, PK11195 in afinal concentration of 20 μmol/L instead of DMSO was added, followed byincubation. In the case of calculating the affinity of the compound ofthe present invention, a DMSO solution of the present invention in afinal concentration of 10 pmol/L to 1 μmol/L instead of DMSO was added,followed by incubation. One hour later, they were sucking filtered inthe above method, and the radioactivity on the filter was measured witha liquid scintillation counter. From the obtained data, theconcentration of the compound of the present invention (IC₅₀ value)needed to inhibit the specific binding amount of [³H]PK11195 by 50% wascalculated. An inhibition constant (K_(i) value) was calculated using aK_(D) value and an IC₅₀ value according to the formula of Cheng andPrusoff (Biochem. Pharmacol. 1973; 22: pp. 3099-3108).

As a result, it was revealed that the compound of the present inventionhad high affinity to MBR.

For example, a K_(i) value of the compound of Example 38 was 0.08 nM.

Biological Example 2 Study on Antistress Effect (1)

Psychological stressor was loaded using a Wistar male rat (Brain Res.1994; 641: pp. 21-28). Water was accumulated by the depth of about 10 cmin a container having a platform in the center. Thirty-minutes after amedium or the compound of the present invention (the compound of Example38) was intravenously administered at a dose of 0.01 mg/kg or orallyadministered at a dose of 1 mg/kg, stressor loading was initiated, andone hour later, the number of dejection was counted (10 animals in eachgroup). The rat administered the compound of the present invention andthe rat to which the stress or was not loaded had little dejection afterone hour. On the other hand, it was revealed that the medium treatmentgroup to which the stressor was loaded showed remarkable dejection (thenumber of dejection: mean number 10.5 by intravenous administration, andmean number 8.5 by oral administration), while the compound of thepresent invention significantly inhibited the number of dejection thanthe medium treatment group (the number of dejection: mean number 8.2 byintravenous administration and mean number 6.2 by oral administration).

As a result, it was found that the compound of the present invention hadan antistress effect.

Biological Example 3

Study on Antistress Effect (2)

Physical stressor was loaded using a male Sprague-Dawley (SD) rat(CHARLES RIVER LABORATORIES JAPAN, INC., 7 week old at being used)(Gastroenterology 1988; 94: pp. 611-622; Jpn. J. Phrmacol. 1998; 77: pp.211-217). Thirty minutes after a medium (0.5% Tween 80 physiologicalsaline) or the compound of the present invention (the compound ofExample 38) was orally administered at a dose of 1 mg/kg, stressorloading was initiated by restraining both anterior branches of the ratwith a binding band (Marvel Ltd.). Evaluation was performed by measuringthe number of dejection 30 and 60 minutes after the initiation ofstressor loading (15 animals in each group). It was revealed that themedium treatment group loaded the stress or showed remarkable dejection(the number of dejection: mean number 10.1 (60 minutes after)), whilethe compound of the present invention significantly inhibited the numberof dejection than the medium treatment group (the number of dejection:mean number 7.5 (60 minutes after)).

As a result, it was found that the compound of the present invention hadan antistress effect.

Biological Example 4 Oral Absorbability of Rat

Using a fasted SD male rat (CHARLES RIVER LABORATORIES JAPAN, INC.),under the condition that the compound of the present invention (thecompound of Example 38) was solubilized, the plasma concentration afteradministration in the tail vein at a dose of 0.1 mg/kg and the plasmaconcentration after gastric gavage administration at a dose of 1 mg/kgwere measured. The blood was collected from a rat jugular vein under anunanesthetized condition 5, 15, and 30 minutes, and 1, 2, 3, 4, 6, and 8hours after intravenous administration, and 15 and 30 minutes, and 1, 2,3, 4, 6, and 8 hours after oral administration. Then the blood wascentrifuged at 3000 rpm for 10 minutes and the supernatant was collectedas plasma. The concentration of the compound in plasma was measured withLC/MS/MS (1100 HPLC System (Agilent Co. Ltd.), API 4000 (MDS SCIEXLtd.)). From the obtained plasma concentration, an area under the curve(AUC, ngh/ml) and a maximum plasma concentration (C_(max), ng/mL) werecalculated. In addition, Bioavailability (B.A.) of the compound of thepresent invention was calculated from AUC in oral administration and AUCin intravenous administration.

As a result, it was found that the compound of the present inventionshowed B.A. of 86.9% and is excellent in oral absorbability.

Biological Example 5 Competition Experiment of MBR Ligand

Using a Wistar male rat, psychological stressor similar to that inBiological Example 2 described above was loaded. Each treatment groupwas set as follows: a medium was intravenously administered (treatmentgroup 1), the compound of the present invention (the compound of Example38) was intravenously administered at a dose of 0.1 mg/kg (treatmentgroup 2), an MBR selective agonist (CB34) was intravenously administeredat a dose of 1 mg/kg (treatment group 3), or after the compound of thepresent invention (the compound of Example 38) was intravenouslyadministered at a dose of 0.1 mg/kg, an MBR selective agonist wasintravenously administered at a dose of 0.1 mg/kg (treatment group 4).In each group, stressor loading was initiated 10 minutes afteradministration, and the number of dejection was counted one hour later(10 animals in each group). The rats in the treatment groups 1, 3, and 4showed remarkable dejection (the number of dejection: treatment group 1(mean number 10.9), treatment group 3 (mean number 9.5), treatment group4 (mean number 10.1)), while the number of dejection was inhibited inthe rat in the treatment group 2 (the number of dejection: mean number7.3). From this result, it was revealed that the effect observed insingle administration of the compound of the present invention wasreduced by administration of the MBR selective agonist.

As a result, it was speculated that the compound of the presentinvention expressed an antistress effect since it had an MBR antagonism.

Biological Example 6 Study on Inhibitory Action on Abdominal Pain in RCSLoading Model

A Wistar male rat (6 week old at being received) was anesthetized withpentobarbital sodium (Kyoritsu Seiyaku Corporation), its abdomen wasincised and the abdominal muscle was exposed, and then Force Transducer(F-12IS-SL (STAR MEDICAL Ltd.)) was fitted. Penicillin was intramuscularadministered after the operation, and a recuperative period of 5 dayswas set.

During from AM 9:00 to PM 5:00 on a 1^(st) day of the initiation ofstress loading, the feeding environment temperature was alternatelychanged to 24° C. and 2° C. in an hour interval, and during from PM 5:00to AM 9:00 in the next morning, the rat was fed under the environment of2° C. From a 2^(nd) day to a 4^(th) day, during AM 9:00 to PM 6:00, thefeeding environment temperature was alternately changed to 24° C. and 2°C. in an hour interval, and during PM 6:00 to AM 9:00 in the nextmorning, the rat was fed under the environment of 2° C. and Repeatedcold stress (RCS) was loaded. A medium or the compound of the presentinvention (the compound of Example 38) was orally administered twice aday at a dose of 1 mg/kg. For the animal to which RCS was not loaded(nonstress loaded rat), a medium was administered.

After RCS was loaded for 4 days, abdominal pain evaluation was performedon a 5^(th) day (10 to 12 animals in each group). At evaluatingabdominal pain, the stress loaded rat and the nonstress loaded ratreceived only an indwelling operation were put in a measuring cage, anda balloon (Fogarty catheter 6F (Baxter Ltd.)) was inserted by about 3 cminto the rectum from the anus and fixed. After confirming that abdominalexercise was stable, the liquid amount in the balloon was stepwiselyincreased to 0, 0.3, 0.6, 0.9, and 1.2 mL in 5 minutes interval.Contraction of abdominal muscle for extension stimulation in eachballoon liquid amount was recorded using the Chart software (Chartv5.0.2. (ADInstruments Inc.)) by passing the signal from the pressuretransducer amplified by the amplifier (Windo Gragf (GOULD Inc.)) throughthe data collection system (PowerLab (ADInstruments Inc.)). During 5minutes in which balloon extension stimulation was loaded, the number ofsignals from the pressure transducer in 3 minutes was counted, and theobtained number was regarded as the number of abdominal musclecontraction and set as the index of abdominal pain. As shown in FIG. 1,for the number of abdominal muscle contraction increased as compared tothe nonstress loaded rat in the medium treatment group, the compound ofthe present invention significantly inhibited the number of abdominalmuscle contraction in all balloon capacities.

As a result, it was found that the compound of the present invention hadan inhibitory action on abdominal pain induced by stress.

Preparation Example 1

The following respective components were mixed by a conventional methodand then compressed into tablets to obtain 10,000 tablets eachcontaining 10 mg of an active ingredient.

-   (1S)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (100 g)-   Carboxymethylcellulose calcium (disintegrant) (20.0 g)-   Magnesium stearate (lubricant) (10.0 g)-   Microcrystalline cellulose (870 g)

Preparation Example 2

The following respective components were mixed by a conventional method,the mixture was filtered by a dust removing filter, filled in an ampulein 5 ml each, and then heat-sterilized using an autoclave to obtain10,000 ampules each containing 20 mg of an active ingredient.

-   (1S)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]    (200 g)-   Mannitol (2 kg)-   Distilled water (50 L)

INDUSTRIAL APPLICABILITY

The compound of the present invention represented by the general formula(I) has affinity for MBR and has an antistress effect, and is thereforeuseful as a preventive and/or therapeutic medicine for diseases causedby stress, particularly digestive system disorders caused by stress.

The invention claimed is:
 1. A method of preparing a compoundrepresented by formula (I-B-1-2):

wherein R¹ is a hydrogen atom, C₁₋₈ alkyl, C₁₋₈ alkoxy, or halogen atomand to is 0 or an integer of 1 to 4; R²⁰¹ is selected from (1) methoxywhich may have a fluorine atom(s), (2) isopropoxy which may have afluorine atom(s), and (3) cyclopentyloxy which may have a fluorineatom(s); R²⁰² is selected from (1) fluorine atom, (2) chlorine atom, (3)cyano, (4) methyl, and (5) methoxy which may have a fluorine atom(s) asalt thereof, an N-oxide thereof, or a solvate thereof the processcomprising: (1) condensing an amine compound of the following formula(A):

with a carboxylic acid of the following formula (B):

in the presence of 1-hydroxy-7-azabensotriazole (HOAt) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), to obtain acompound of the following formula (C):

(2) subjecting the compound of formula (C) to a cyclization reaction inthe presence of phosphorous oxychloride to obtain a compound of thefollowing formula (D):

(3) Reducing the compound of the formula (D) in the presence of sodiumborohydride to obtain a compound of the following formula (II)′:

(4) subjecting the compound of the formula (II)′ to an amidationreaction in the presence of pyridine and acetic anhydride.
 2. The methodaccording to claim 1, wherein the compound prepared is a compoundrepresented by formula (I-B-1-2-a):

wherein all symbols have the same meanings as described in claim 1, asalt thereof, an N-oxide thereof, or a solvate thereof.
 3. The accordingto claim 1, wherein the compound prepared is (2)2-acetyl-1-(2,4-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(3)2-acetyl-1-(3,4-difluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(4)2-acetyl-1-(3-fluorophenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(5)2-acetyl-6-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(6)2-acetyl-1-(2,4-difluorophenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(7)2-acetyl-1-(3,4-difluorophenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(8)2-acetyl-1-(3-fluorophenyl)-7-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(9)2-acetyl-7-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(10)2-acetyl-1-(3-fluorophenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(19)2-acetyl-1-(3-fluorophenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(20)2-acetyl-1-(2,4-difluorophenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(21)2-acetyl-1-(2,4-difluorophenyl)-7-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(22)2-acetyl-1-(3,4-difluorophenyl)-7-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(23)2-acetyl-5-fluoro-1-(3-fluorophenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(24)2-acetyl-1-(2,4-difluorophenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(25)2-acetyl-1-(3,4-difluorophenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(26)2-acetyl-1-(3-fluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(27)2-acetyl-1-(2,4-difluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(28)2-acetyl-1-(3,4-difluorophenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(29)2-acetyl-1-(3-fluorophenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(30)2-acetyl-1-(3,4-difluorophenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(38)7′-acetyl-8′-(3-fluorophenyl)-1′-methyl-1′,6′,7′,8′-tetrahydrospiro[cyclopropane-1,5′-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine,(47)2-acetyl-5-methoxy-1-(2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[beta-carboline-4,1′-cyclopropane],or (48)4-(2-acetyl-5-methoxy-1,2,3,9-tetrahydrospiro[beta-carboline-4,1′-cyclopropane]-1-yl)benzonitrile,a salt thereof, an N-oxide thereof, or a solvate thereof.
 4. The methodaccording to claim 1, which wherein the compound prepared is (1)2-acetyl-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(2)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(3)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-difluoro-1,2,3,9-tetrahydrospiro[f3-carboline-4,1′-cyclopropane],(4)2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(5)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(6)2-acetyl-5-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(7)2-acetyl-5-chloro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(8)2-acetyl-5-fluoro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(9)2-acetyl-6-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(10)2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(11)2-acetyl-1-(5-fluoro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(12)2-acetyl-1-(4-fluoro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(13)2-acetyl-1-(2,4-dimethoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane](14)2-acetyl-1-(2-fluoro-6-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(15)2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(16)2-acetyl-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(17)2-acetyl-5-fluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(18)2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(19)2-acetyl-1-(4-fluoro-2-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(20)2-acetyl-6-methoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(21)2-acetyl-1-(2-fluoro-6-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(22)2-acetyl-6,7-dimethoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(23)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(24)2-acetyl-1-(2-methoxy-4-methylphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(26)2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(27)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(28)(1S)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(29)(−)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(30)(+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,6-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(31)(+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(32)(+)-2-acetyl-1-(2-fluoro-6-methoxyphenyl)-5-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(33)(+)-2-acetyl-5-fluoro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(34)(+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,7-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(35)2-acetyl-5-chloro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(36)2-acetyl-5,6-difluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(37)2-acetyl-5,6-difluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(38)2-acetyl-5-chloro-1-(2-fluoro-6-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(39)2-acetyl-1-(4-chloro-2-isopropoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(40)2-acetyl-1-[4-chloro-2-(cyclopentyloxy)phenyl]-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(41)4-(2-acetyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)-3-methoxybenzonitrile,(42)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5,7-difluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(43)2-acetyl-1-(4-chloro-2-methoxyphenyl)-8-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(44)4-(2-acetyl-5-fluoro-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane]-1-yl)-3-methoxybenzonitrile,(45)2-acetyl-5,6-dimethoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(47)2-acetyl-5-methoxy-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(48)2-acetyl-1-(4-chloro-2-methoxyphenyl)-6,8-dimethoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(49)2-acetyl-6-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(50)2-acetyl-1-(4-chloro-2-methoxyphenyl)-5-fluoro-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(51)2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-8-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(52)(+)-2-acetyl-1-(2-fluoro-6-methoxyphenyl)-6-methoxy-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(53)(+)-2-acetyl-1-(2-methoxy-4-methylphenyl)-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(54)(+)-2-acetyl-1-(4-chloro-2-methoxyphenyl)-6-methoxy-5-methyl-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(55)(+)-2-acetyl-5-fluoro-1-(4-fluoro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],(56)(+)-2-acetyl-5,6-difluoro-1-(2-methoxy-4-methylphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],or (57)(+)-2-acetyl-5-chloro-1-(4-chloro-2-methoxyphenyl)-1,2,3,9-tetrahydrospiro[β-carboline-4,1′-cyclopropane],a salt thereof, an N-oxide thereof, or a solvate thereof.